Exercise Biology of Neuromuscular Disorders...83 readers are directed to excellent papers on this...

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Exercise Biology of Neuromuscular Disorders

Journal: Applied Physiology, Nutrition, and Metabolism

Manuscript ID apnm-2018-0229.R1

Manuscript Type: Review

Date Submitted by the Author: 18-Jun-2018

Complete List of Authors: Ng, Sean; McMaster University, Kinesiology Manta, Alexander; McMaster University, Kinesiology Ljubicic, Vladimir; McMaster University, Kinesiology

Is the invited manuscript for consideration in a Special

Issue? : Nervous System and Exercise

Keyword: Duchenne muscular dystrophy, Spinal muscular atrophy, Myotonic dystrophy type 1, AMPK, PGC-1α

https://mc06.manuscriptcentral.com/apnm-pubs

Applied Physiology, Nutrition, and Metabolism

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Exercise Biology of Neuromuscular Disorders 1

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Sean Y Ng, Alexander Manta, and Vladimir Ljubicic 4

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Department of Kinesiology, McMaster University, Hamilton, Ontario, Canada 6

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Correspondence: 16

Vladimir Ljubicic, PhD 17

Department of Kinesiology 18

McMaster University 19

Hamilton, ON, L8S 4L8, Canada 20

Tel: 905 525 9140 ext. 24517 21

Email: [email protected]

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Abstract 23

Neuromuscular disorders (NMDs) are chronic conditions that affect the neuromuscular 24

system. Many NMDs currently have no cure, however as more effective therapies become 25

available for NMD patients, these individuals will exhibit prolonged health- and/or lifespans. As 26

a result, persons with NMDs will likely desire to engage in a more diverse variety of activities of 27

daily living, including increased physical activity or exercise. Therefore, there is a need to 28

increase our knowledge of the effects of acute exercise and chronic training on the 29

neuromuscular system in NMD contexts. Here, we discuss the disease mechanisms and exercise 30

biology of Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and 31

myotonic dystrophy type 1 (DM1), which are among the most prevalent NMDs in children and 32

adults. Evidence from clinical and pre-clinical studies are reviewed, with emphasis on the 33

functional outcomes of exercise, as well as on the putative cellular mechanisms that drive 34

exercise-induced remodeling of the neuromuscular system. Continued investigation of the 35

molecular mechanisms of exercise adaptation in DMD, SMA, and DM1 will assist in enhancing 36

our understanding of the biology of these most prevalent NMDs. This information may also be 37

useful for guiding the development of novel therapeutic targets for future pursuit. 38

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Keywords 40

Duchenne muscular dystrophy, spinal muscular atrophy, myotonic dystrophy type 1, AMPK, 41

PGC-1α 42

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Introduction 44

Neuromuscular disorders (NMDs) are a heterogeneous group of inherited or acquired 45

conditions that affect one or more components of the motor unit, which comprises the 46

motoneuron, neuromuscular junction (NMJ), and skeletal muscle. Approximately 1 in 3,000 47

individuals are affected by these disorders, many of which are progressive, health- and life-48

limiting (Emery 1991). As such, the economic costs of the most prevalent NMDs, such as 49

Duchenne muscular dystrophy (DMD), spinal muscular atrophy (SMA), and myotonic dystrophy 50

(DM) type 1 are significant for patients and their caregivers ($30,000-$65,000/year), as well as 51

for government health care systems (~$0.5-1billion/year) (Armstrong et al. 2016). The 52

economic, social, and emotional burden associated with these conditions, combined with the 53

actuality that most NMDs currently have no cure, emphasize the urgency to address unmet 54

clinical needs and research knowledge gaps. 55

Among the most common signs associated with NMDs are skeletal muscle weakness 56

and wasting. Myofiber atrophy may be primarily cell-autonomous, as observed for example in 57

DMD, or it may occur secondary to degeneration of the innervating motoneuron, for instance in 58

amyotrophic lateral sclerosis. Furthermore, the pathophysiology of SMA demonstrates that 59

decrements in muscle quality and quantity occur via a combination of muscle and motoneuron 60

dysfunction (Hamilton and Gillingwater 2013). The heterogeneity and complexity of this group 61

of diseases is evidenced by conditions such as SMA and DM1, which present not only with 62

neuromuscular impairments, but also with multi-system dysfunction, including cardiovascular 63

and respiratory systems, as well as bone, cognitive, pancreatic, and gastrointestinal 64

complications (Hamilton and Gillingwater 2013, Chau and Kalsotra 2015, Guiraud and Davies 65

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2017). Current approaches to treat NMDs are predominantly symptomatic. New generation 66

therapeutics, such as antisense oligonucleotide (ASO)- and adeno-associated virus-based gene 67

therapy technologies (Rinaldi and Wood 2017), as well as small molecules, highlight the recent 68

progress that has been made in treating NMDs. In fact, some of these, including Spinraza 69

(nusinersen), Exondys 51 (eteplirsen), and Translarna (ataluren), have been recently approved by 70

the US Federal Drug Administration or the European Medicine Agency (Rinaldi and Wood 71

2017). These strategies are not without their limitations however, including selective temporal 72

therapeutic windows, narrowly defined target patient populations, as well as only modest 73

efficacy in some instances (Havens and Hastings 2016). Knowledge gained from continued 74

clinical trials of novel therapeutics in NMD patients, as well as the reverse translation of these 75

findings into additional basic and pre-clinical studies, will likely assist in identifying more 76

effective curative strategies. 77

As NMD patients adopt novel contemporary and future therapies, these individuals will 78

undoubtedly exhibit prolonged health- and lifespans. It is very likely in this scenario therefore, 79

that people with NMDs will embrace more active lifestyles. Thus, there is a critical need to 80

expand our understanding of the effects of acute exercise and chronic training in NMD contexts. 81

The exercise physiology of NMDs, in general, has been discussed previously, and interested 82

readers are directed to excellent papers on this topic (Krivickas 2003, Anziska and Sternberg 83

2013). Moreover, the genetics and molecular biology of various NMDs, including current 84

therapeutic technologies being examined therein, have been recently surveyed in detail elsewhere 85

(Bowerman et al. 2017, Thornton et al. 2017, Guiraud and Davies 2017), and it is not within the 86

scope of the current review to rigorously outline these further. Our goals here are first to provide 87

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an overview of the disease mechanisms of DMD, SMA, and DM1, which are among the most 88

prevalent NMDs. We follow this introduction to each NMD with a discussion of the exercise 89

biology of the condition, including physiological, cellular, and molecular evidence gleaned from 90

clinical and pre-clinical studies. In closing, we submit research questions on the exercise biology 91

of DMD, SMA and DM1 that require further investigation. 92

Duchenne muscular dystrophy 93

DMD is an X-linked disorder affecting ~1/3,500 male births, making it the most common 94

lethal hereditary disease (Birnkrant et al. 2018). DMD is characterized by proximal muscle 95

weakness and wasting leading to loss of ambulation in the second decade of life and death by the 96

third decade as a result of associated respiratory or cardiovascular complications. The molecular 97

basis of DMD is a mutation in the DMD gene resulting in the absence of dystrophin protein 98

(Birnkrant et al. 2018). In skeletal muscle, dystrophin is localized to the sarcolemma as part of 99

the dystrophin-associated protein complex (DAPC), a heterogenous transmembrane cluster with 100

a variety of roles including stabilization between the cytoskeleton and extracellular matrix, as 101

well as involvement in inter- and intracellular signalling (Guiraud and Davies 2017). The loss of 102

dystrophin disrupts the DAPC rendering the sarcolemma susceptible to repeated mechanical-103

induced damage (Guiraud and Davies 2017). With each muscle contraction, large influxes of 104

extracellular calcium (Ca2+) enter the cell, which when combined with dysfunctional intracellular 105

Ca2+ buffering, create a permissive environment for Ca2+-sensitive proteases to ravage the 106

myofiber. Repeated cycling of muscle degeneration followed by muscle stem cell-mediated 107

regeneration eventually fails, which fosters the replacement of myocytes with noncontractile 108

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fibrotic tissue and fatty infiltrate (Ljubicic et al. 2014, Birnkrant et al. 2018). This pathological 109

muscle remodelling accounts for the wasting and weakness observed in DMD patients. 110

The only effective treatment available for DMD is glucocorticoids. These compounds 111

slow the decline in muscle strength and function and delay the onset of respiratory, cardiac and 112

orthopaedic complications (Birnkrant et al. 2018). Additionally, management of joint 113

contractures and muscle extensibility through physiotherapy/rehabilitation is recommended 114

during both the ambulatory and non-ambulatory phases (Birnkrant et al. 2018). Experimental 115

studies support the use of gene-based therapies or small molecule treatments that aim to address 116

the primary dystrophin deficiency or mitigate the resulting downstream sequelae (Guiraud and 117

Davies 2017). For example, ASOs, like the recently FDA-approved Exondys 51, serve to restore 118

the correct reading frame of the DMD gene by inducing the skipping of exons adjacent to 119

mutation sites. This, at best, produces a Becker muscular dystrophy-like phenotype, which is a 120

less severe form of DMD caused by mutations that result in truncated but still somewhat 121

functional dystrophin protein. A prevailing hypothesis asserts that therapies that are independent 122

of the specific DMD-causing dystrophin mutation will be able to reach more DMD cases 123

(Ljubicic et al. 2014, Guiraud and Davies 2017). Consistent with this, there is a strong body of 124

evidence to suggest that increasing the expression in muscle of utrophin, an endogenous 125

structural homologue of dystrophin, can mitigate the dystrophic phenotype (Dial et al. 2018, 126

Ljubicic et al. 2014). Unlike dystrophin, utrophin is largely confined to the neuromuscular 127

junction and myotendinous junction in skeletal muscle. Notably, utrophin is expressed at a 128

significantly higher level in slow, oxidative myofibers, compared to their faster, more glycolytic 129

counterparts. Furthermore, utrophin content is also enriched in extrasynaptic regions in slower, 130

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more oxidative myofibers. This fiber type-specific utrophin expression pattern accounts, in part, 131

for the greater degree of protection exhibited by slow, oxidative muscles against the dystrophic 132

pathology (Ljubicic et al. 2014). Enhanced mitochondrial biogenesis and function, characteristics 133

more typical of slow, oxidative muscle, as compared to fast, glycolytic tissue, also alleviate 134

DMD (Ljubicic et al. 2014). Therefore, interventions that promote a phenotype shift towards a 135

slower, more oxidative fiber type, which includes utrophin upregulation, may be an effective 136

therapeutic approach in DMD. 137

Exercise in DMD 138

Although there still remain critical knowledge gaps with respect to the effects of chronic 139

exercise on cardiac and respiratory muscle function in DMD patients (Spaulding and Selsby 140

2018), mild, habitual physical activity is a therapeutic modality that complements current 141

neuromuscular (e.g., glucocorticoids) and rehabilitation (e.g., mobility devices) management 142

strategies for DMD patients (Hyzewicz et al. 2015, Birnkrant et al. 2018, Kostek and Gordon 143

2018). For instance, the gold standard No Use is Disuse study by Jansen et al. (2013) 144

demonstrated that assisted bicycle exercise training modestly, but significantly preserved muscle 145

function in boys with DMD. As thoroughly discussed in recent, excellent contributions by 146

Spaulding and Selsby (2018), Kostek and Gordon (2018), as well as Hyzewicz and colleagues 147

(2015), exercise merits a more thorough evaluation as part of a holistic approach to improved 148

patient care since in healthy individuals exercise produces beneficial adaptations to processes 149

that are perturbed in DMD such as inflammation (Beavers et al. 2010), intracellular calcium 150

homeostasis (Stammers et al. 2015) and oxidative stress (Powers et al. 2011). Thus, in light of 151

these recent, comprehensive reviews on exercise in pre-clinical DMD models and DMD 152

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participants (Hyzewicz et al. 2015, Kostek and Gordon 2018, Spaulding and Selsby 2018), which 153

readers are encouraged to peruse, here we focus on the potential molecular mechanisms of 154

exercise adaptation in dystrophic skeletal muscle. The identification of exercise-induced cellular 155

pathways that drive adaptive changes in DMD might provide valuable information for the 156

development of novel pharmacological therapies. 157

Mechanisms of exercise adaptation in dystrophic skeletal muscle 158

In the healthy condition, exercise activates 5' adenosine monophosphate (AMP) -159

activated protein kinase (AMPK) via ATP depletion and the reciprocal elevations of AMP and 160

ADP. Chronic AMPK activation drives phenotypic remodelling in muscle through the regulation 161

of transcription factors and coregulators (Egan and Zierath 2013). For example, AMPK 162

phosphorylates and activates peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α 163

(PGC-1α), a transcriptional coactivator and master regulator of neuromuscular plasticity. PGC-164

1α coactivates numerous genes indicative of the slow, oxidative myogenic program, as well as 165

participates in a feed-forward loop via autoregulation. PGC-1α activity and expression are also 166

robustly stimulated by exercise (Egan and Zierath 2013). In addition to AMPK and PGC-1α, 167

molecules such as p38 mitogen-activated protein kinase (p38), calcineurin (CN), PPARδ, and 168

silent mating type information regulator 2 homolog 1 (SIRT1), are evoked by exercise (Egan and 169

Zierath 2013) and have been implicated in a variety of cellular functions that mitigate the 170

dystrophic pathology (Ljubicic et al., 2014). These processes include the regulation of 171

autophagy, improved myocellular Ca2+ handling, stimulation of mitochondrial biogenesis and 172

function, as well as other markers of the slow, oxidative phenotype, such as utrophin expression, 173

and induction of heat shock protein (HSP) content and activity (Ljubicic et al. 2014). 174

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A single bout of exercise in mdx mice stimulates skeletal muscle AMPK and p38 175

phosphorylation status, and induces the mRNAs of PPARδ, PGC-1α, and SIRT1 (Ljubicic et al. 176

2014). Beyond this unfortunately, the mechanisms of exercise-induced muscle remodelling in 177

DMD are unknown. It is reasonable to hypothesize however, that the molecular pathways that 178

mediate acute exercise responses and training adaptations in the healthy condition, such as 179

AMPK, PGC-1α, and PPARδ, might also do so in dystrophic muscle (Figure 1). Indeed, studies 180

that genetically or pharmacologically activate these molecules support this concept. For instance, 181

chronic treatment of mdx mice with the AMPK activator 5-aminoimidazole-4-carboxamide-1-β-182

d-ribofuranoside (AICAR) significantly increased utrophin expression along with increased 183

markers of muscle oxidative capacity and induced a shift towards a slower muscle fiber type (Al-184

Rewashdy et al. 2015). Additionally, AMPK stimulation conferred a significant reduction in 185

central nucleation, improved forelimb grip strength and decreased susceptibility to contractile-186

induced damage. Chronic AICAR administration also simulates corrective autophagy and 187

ameliorates muscular dystrophy in mdx animals (Dial et al., 2018, Ljubicic et al., 2014). 188

Classic studies by the Jasmin and Spiegelman laboratories demonstrated that PGC-1α 189

upregulates the expression of utrophin along with other genes associated with the neuromuscular 190

junction (Angus et al. 2005, Handschin et al. 2007). Additionally, Handschin et al. showed that 191

transgenic skeletal muscle-specific overexpression of the coactivator in mdx mice reduced 192

numerous dystrophic indicators, such as centrally-located myonuclei and serum creatine kinase. 193

These animals were also able to outperform mdx mice in a downhill running protocol, while 194

exhibiting reduced signs of eccentric contraction-induced muscle damage. Similar alleviation of 195

the dystrophic pathology was observed in mdx mice that overexpressed SIRT1 in muscle 196

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(Chalkiadaki et al. 2014). Employing a more translatable methodology, Miura and colleagues 197

demonstrated that chronic pharmacological PPARδ stimulation was effective at enhancing 198

skeletal muscle utrophin content, coincident with evoking the slow, oxidative myogenic program 199

in mdx mice (Miura et al. 2009). These molecular adaptations were associated with augmented 200

muscle structure and function, as evidenced by an attenuation of the force drop caused by 201

eccentric muscle contractions, as well as reduced contraction-induced sarcolemmal lesions. 202

Pharmacological p38 activation with chronic heparin administration significantly augments 203

utrophin protein expression in the mdx diaphragm (Amirouche et al. 2013). This is likely 204

mediated, in part, by a post-transcriptional mechanism involving the enhanced stability of 205

utrophin mRNA via the suppression of K homology splicing regulator protein (KSRP) activity. 206

As elegantly and comprehensively summarized by Michel (2007) and Lynch (2017), the 207

Ca2+-sensitive phosphatase CN and its downstream transcription factor target nuclear factor of 208

activated T cells (NFAT) form the distal segment of a Ca2+-regulated pathway that drives 209

expression of the slow, oxidative myogenic program in dystrophic muscle. In short, CN permits 210

NFAT to bind to the utrophin promoter and drive its expression in extrasynaptic regions of 211

myofibers, which ultimately contributes to the augmented membrane stability, force-producing 212

capacity, and improved histopathology in mdx mice engineered to exhibit elevated CN 213

expression and activity. Dysregulated Ca2+ handling accounts for a significant share of the 214

degenerative cascade in dystrophic muscle (Allen et al. 2016). HSPs have been shown to 215

promote the restoration of Ca2+ homeostasis, as well as to mitigate other features associated with 216

the dystrophic pathology such as inflammation (Thakur et al. 2018). Gehrig and colleagues 217

(2012) demonstrated that inducing HSPs, by either pharmacological or genetic means, preserves 218

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muscle function and slows progression of muscular dystrophy in mdx animals, as well as in the 219

more severe dystrophin/utrophin double-knockout mice. Collectively, the evidence clearly 220

indicates that the genetic or pharmacological activation of numerous molecules in dystrophic 221

muscle, indeed those same proteins that are stimulated by exercise in the healthy condition, 222

beneficially remodel the dystrophic phenotype in pre-clinical contexts. Future studies should aim 223

to elucidate exercise-evoked mechanisms of adaptation, including whether recently discovered 224

DMD disease modifiers, such as osteopontin, α-actinin-3, Jagged 1, or latent TGF-β-binding 225

protein 4 are impacted by physical activity (Hightower and Alexander 2017). 226

Spinal muscular atrophy 227

SMA is the leading genetic cause of infant mortality and the second most prevalent 228

autosomal recessive disorder after cystic fibrosis (Awano et al. 2014). This health- and/or life-229

limiting disorder occurs at ~1/10,000 live births. The most common and severe types I and II 230

SMA account for approximately ~85% of all cases (Awano et al. 2014). These patients 231

experience significant cardiorespiratory complications and most die ~24-36 months after birth 232

(Awano et al. 2014). The less severe types III and IV SMA represent ~15% of the total and are 233

diagnosed as early as 18 months old. Although patients with milder SMA generally live well into 234

adulthood, a spectrum of motor impairments and secondary complications may manifest. 235

SMA is caused by homozygous mutations in the survival motor neuron (SMN) 1 gene, 236

which encodes SMN protein (Hamilton and Gillingwater 2013). SMN protein has many 237

important functions, including primarily spliceosome biogenesis (Bowerman et al. 2017). 238

Mutations in SMN1 cause patients to rely solely on the virtually identical SMN2 gene to produce 239

SMN protein. However, the majority (~80-90%) of SMN transcripts from SMN2 are truncated 240

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due to a C-to-T substitution at position 840 of exon 7. Despite being a translationally silent 241

difference, it nevertheless repeals the 5’ exonic splicing enhancer, which causes the spliceosome 242

machinery to exclude exon 7 from the mature SMN mRNA (Hamilton and Gillingwater 2013, 243

Bowerman et al. 2017). Consequently, these truncated SMN transcripts, known as SMN∆7, are 244

translated into similarly contracted and rapidly degraded SMN∆7 protein. However, ~10-20% of 245

SMN mRNA transcribed from SMN2 are full-length (FL) transcripts, which are synthesized into 246

functional FL-SMN protein. At present, the abundance of FL-SMN expressed from SMN2 genes 247

is the primary disease modifier in SMA. 248

The cardinal signs of SMA are the degeneration and death of α-motoneurons (αMNs), 249

NMJ dysfunction, as well as skeletal muscle wasting and weakness (Hamilton and Gillingwater 250

2013). While increasing FL-SMN abundance in the spinal cord (SC) certainly increases health, 251

fitness, and longevity in mice with SMA, optimal mitigation of the pathology necessitates 252

augmented FL-SMN levels in peripheral tissues including skeletal muscle (Bowerman et al. 253

2017). Thus, an intervention that elicits systemic effects, including the targeting of αMNs and 254

skeletal muscle in particular, should be considered when designing therapeutic strategies for 255

SMA (Talbot and Tizzano 2017). 256

The therapeutic efficacy of exercise in SMA patients 257

To our knowledge, the first study to report on the effects of chronic physical activity 258

specifically in SMA patients was by McCartney and colleagues (1988) in 1988. Here, a small 259

cohort (n = 3) of individuals with relatively mild SMA completed a nine week, three times/week, 260

progressive resistance exercise program, consisting of four sets of elbow flexion and bilateral leg 261

press not exceeding 70% maximal voluntary contraction. The authors observed that training lead 262

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to improved dynamic strength in the arms and legs, greater isokinetic torque generation, and 263

enhanced elbow flexor contractile properties. Furthermore, positive outcomes on feasibility 264

metrics, such as signs of muscular damage, validated the tolerability and safety of exercise in this 265

population despite the fact that historically, SMA patients have been advised against engaging in 266

exercise training to avoid possible exacerbation of neuromuscular damage (Krivickas 2003, 267

Anziska and Sternberg 2013). 268

Work by Lewelt and colleagues (2015) investigated the effects of a twelve week, 269

progressive resistance training program, three times/week, in a larger group (n = 9) of children 270

and adolescents with type II or type III SMA. In parallel with the previous literature, participant 271

adherence was high (~90%) while training sessions were ~99% pain-free and no study-related 272

adverse events occurred, reinforcing the notion that training is feasible and safe in SMA patients. 273

Modest, but statistically significant training-induced increases in muscle strength were observed 274

in the manual muscle testing of upper and lower body movements. Notably, motor function, 275

evaluated with the Modified Hammersmith Functional Motor Scale-Extend, was also improved 276

after training. The small sample sizes notwithstanding, these well-designed and -executed studies 277

provide assurance that progressive resistance exercise training can be performed safely and 278

without risk of harm, as well as demonstrate favorable adaptations in children, adolescents, and 279

adults with SMA. 280

Endurance-type exercise training also elicits improvements in SMA patients. For 281

example, Madsen et al. (2015) introduced a twelve week, home-based aerobic training program 282

to a small cohort (n = 6) of type III SMA patients. Training was composed of 30-minute sessions 283

on a cycle ergometer at 60-75% of predicted VO2max three times/week. Chronic exercise 284

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significantly improved fitness (i.e., ~30% increase in VO2max) without any increase in plasma 285

creatine kinase levels, which would be indicative of training-induced muscle damage. Despite 286

the increase in fitness observed in patients, there were no significant changes in functional 287

outcomes, including the 6-minute walk test or the timed up-and-go. It is important to note here 288

that all participants reported either no change or an increased feeling of fatigue in the activities of 289

daily living (ADL) questionnaire. These results clearly indicate that careful consideration should 290

be applied to the selection of training variables (i.e., frequency, intensity, time, type) in order to 291

circumvent fatigue. 292

Endurance-type training adaptations in SMA patients are further described in a recent 293

twelve week training study with non-ambulatory 4-7 year-olds with type II SMA (Bora et al. 294

2018). Here, participants (n = 5) performed 30 minutes of supervised arm cycling exercise at 295

60% of their maximum heart rate three times/week. The authors reported that the exercise regime 296

was well tolerated, and that a significant improvement in endurance capacity was observed, as 297

evidenced by augmented cycling distance and duration. Peripheral blood mononuclear cells were 298

assayed for SMN expression, which revealed no alterations in SMN protein content over the 299

course of the training program. Unfortunately, this analysis was not conducted in commonly 300

biopsied peripheral tissues, such as skin or skeletal muscle, where SMN levels represent a more 301

accurate biomarker of disease status. Finally, Montes and colleagues (2015) recently investigated 302

the effects of combined aerobic and strengthening exercises in a Type III SMA patient cohort (n 303

= 12) aged 10-48 years old. Participants performed aerobic, endurance-type exercise on a 304

recumbent cycle ergometer five times/week, 30 minutes/day, whereas resistance-type exercise 305

was performed three times/week with similar target duration. The investigation did not uncover 306

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any deleterious effects of chronic exercise on strength, function, or fatigue. Further, all testing 307

and intervention procedures were well tolerated without any serious adverse events. Percent-308

predicted VO2max increased significantly (+5%) in the trained group compared to their control, 309

sedentary counterparts, while modest, but not statistically significant improvements were 310

observed in strength and functional measures in the trained SMA participants. The authors 311

suspected that these small training-induced adaptations were partly due to impaired 312

neuromuscular mitochondrial biogenesis and function. More work is required to address this 313

interesting hypothesis. 314

Collectively, these studies demonstrate that both resistance- and endurance-type exercise 315

programs are feasible, safe, and well tolerated in children, adolescents, and adults with SMA 316

(Table 1). It is certainly worth noting that due to their small cohort sizes, the results of these 317

important studies should be interpreted with some caution. Moreover, the clinical significance of 318

enhanced fitness concomitant with limited improvements in strength and motor function 319

observed in these studies remains unclear. However, the potential long-term benefit of increased 320

fitness, strength, and function is clear. In addition, these investigations provide important 321

guidance for clinical management of SMA patients and inform future study design of exercise in 322

SMA. 323

The molecular mechanisms of exercise adaptations in SMA 324

Examination of the molecular mechanisms that drive exercise-induced neuromuscular 325

remodeling in SMA is important because it increases our understanding of the basic biology of 326

the disease, as well as facilitates the discovery of novel targets for future therapeutic 327

investigation. Unfortunately, to date, no studies have pursued this cause in SMA patients. To 328

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address this knowledge gap, Frédéric Charbonnier and colleagues published a series of elegant 329

pre-clinical studies that explore the mechanisms of exercise adaptation in the neuromuscular 330

system of SMA mice (Biondi et al., 2008; Chali et al., 2016; Grondard et al., 2005; Biondi et al., 331

2015). Grondard et al. (2005) was the first of these to detail exercise-induced molecular 332

adaptations in mice with SMA. These animals, which recapitulated a relatively severe type II-333

like SMA phenotype, were subjected to a daily running program on a motor-driven running 334

wheel beginning at postnatal day (P) 10. The trained animals exhibited improved clinical 335

outcomes, including a ~60% prolonged survival rate, diminished muscle weakness, as well as 336

enhanced motor behavior, as compared to sedentary SMA mice. Furthermore, the authors 337

observed greater FL-SMN mRNA levels in the lumbar SC, as well as reduced loss of αMNs and 338

skeletal muscle atrophy in the chronically active SMA mice. Remarkably, these training-evoked 339

adaptations were revealed after as little as 3 days of running, which suggests that the upstream 340

molecular machinery required to elicit these changes is intact and highly responsive in the SMA 341

context. Biondi and colleagues (2008) later elaborate on a molecular mechanism driving these 342

exercise-induced adaptations with a similar exercise protocol and SMA murine model. Here, 343

daily exercise positively influenced NMJ morphology and transmission efficiency, while 344

preserving αMNs in the soleus, plantaris, and tibialis anterior muscles of SMA mice. The authors 345

also observed an increase in lumbar SC N-methyl-D-aspartate receptor (NMDAR) GluR epsilon 346

1 (NR2A) expression, a subunit of the NMDAR, in the trained SMA mice relative to the 347

sedentary SMA group. To test whether the beneficial effects of exercise were dependent on the 348

NMDAR, the specific noncompetitive NMDAR antagonist, MK-801, was then utilized. 349

NMDAR blockade resulted in a significant reduction in the exercise-induced increase in 350

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survival, as well as mitigated training-evoked adaptations in αMNs and skeletal muscle. 351

Together, these data highlight an important role for the NMDAR in exercise-induced 352

neuromuscular plasticity in type II-like SMA mice. 353

A methodological challenge to using the type II SMA-like mice described in these 354

studies is the rapid disease progression beginning at ~P9 and thus the relatively short lifespan of 355

~14 days. This short treatment window also limits the translational capacity of these exercise 356

studies to the human SMA condition. To address these concerns, Chali and colleagues (2016) 357

subjected mild SMA type III-like mice, which exhibit a typical lifespan, to a running- or 358

swimming-based exercise training program for 10 months. They observed significant increases 359

in muscle strength and endurance in response to both interventions. αMNs in the ventral horn of 360

the SC were preserved in both trained SMA groups, as was NMJ structure and function. 361

Interestingly, significant differences in the presence and/or magnitude of training-induced 362

adaptations were observed between run and swim exercise. For example, the loss of larger, faster 363

Chodl+ αMNs was limited by swimming only, whereas running selectively preserved ERRβ+ 364

small, slower αMNs. It is important to note that all of the beneficial changes elicited by training, 365

regardless of mode, emerged without changes in ventral lumbar SC SMN content. Whether there 366

were alterations in skeletal muscle SMN levels was not reported. This study indicates that, at 367

least in a relatively less severe model of SMA, the neuromuscular benefits of exercise training 368

can occur in a SC SMN-independent fashion. This finding is not unprecedented, as improvement 369

in NMJ biology and attenuated αMN attrition have been previously shown in SMA animals 370

without accompanying elevations in SMN content (Talbot and Tizzano 2017). 371

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Finally, Biondi et al. (2015) revealed some of the upstream, transcriptional mechanisms 372

driving exercise-induced neuromuscular remodeling in SMA mice. Consistent with their 373

previous work, the authors observed a rise in SMN protein in the SC with exercise training in 374

type II-like SMA mice. The elevation in FL-SMN expression could be attributed to enhanced 375

Ca2+/calmodulin-dependent protein kinase II-protein kinase B (AKT)-cAMP response element-376

binding protein (CREB) axis signaling, which was likely mediated, in part, by a reduction in 377

insulin-like growth factor-1 receptor (IGF-1R) content and downstream function. Furthermore, it 378

was hypothesized that exercise-evoked downregulation of IGF-1R would attenuate extracellular 379

signal-regulated kinase (ERK) and E26 transformation-specific domain-containing protein 380

(ELK-1) activities, which serve to repress FL-SMN induction from SMN2. This was supported 381

by experiments in which SMA mice engineered with a knockdown of IGF-1R demonstrated 382

increased CREB and reduced ELK-1 at the SMN2 promoter, which was associated with 383

augmented FL-SMN expression. The increased FL-SMN in the SMA/IGF-1R KO mice evoked 384

similar exercise training-induced adaptations as those described by Grondard and colleagues 385

above (2005), including improved motor function, preserved αMN content, and prolonged 386

lifespan. Taken together, these studies by Charbonnier and colleagues provide a molecular basis 387

for our understanding of how chronic exercise positively affects physiology and function in 388

SMA (Figure 2). 389

AMPK and p38 MAPK might also act as alternative upstream mediators that contribute 390

to exercise training adaptations in SMA (Dial et al., 2018). It is well established that endurance-391

type exercise training-induced benefits in healthy individuals occur due to, in part, the chronic 392

activation of these enzymes (Egan and Zierath 2013). Chronic AICAR administration protects 393

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NMJ morphology, as well as elicits increased myofiber size and greater proportions of type I 394

fibres in relatively severe type I/II-like SMA mice, while treatment with the p38 activator 395

celecoxib induces SMN mRNA stabilization by a human antigen R (HuR) protein dependent-396

manner in the brain and SC of these animals (Farooq et al. 2013, Cerveró et al. 2016). Based on 397

these studies, it is therefore reasonable to hypothesize that AMPK- and p38-mediated signaling 398

are among the mechanisms responsible for driving exercise adaptation in SMA (Figure 2). 399

Additional work is necessary to confirm this, as well as to describe the SMN-dependent and -400

independent pathways by which training preserves or improves neuromuscular health and 401

prolongs lifespan in SMA. 402

Myotonic dystrophy type 1 403

DM1 is the most common MD in adults and is the second most prevalent MD after DMD 404

with an incidence of ~1/8,000 worldwide (Chau and Kalsotra 2015). It is an autosomal dominant 405

trinucleotide repeat disease with multisystem involvement, prominently characterized by skeletal 406

muscle weakness, wasting, myotonia and insulin resistance (Cho and Tapscott 2007). DM1 407

arises from a CTG microsatellite repeat expansion mutation in the 3’ untranslated region (UTR) 408

of the dystrophia myotonica protein kinase (DMPK) gene (Chau and Kalsotra 2015). The 409

phenomena of genetic instability and anticipation are common in DM1, which along with the 410

occurrence of upstream CpG methylation, help explain the mechanisms underlying the various 411

forms of DM1, including congenital, juvenile, and the more common adult-onset (Nakamori et 412

al. 2013, Chau and Kalsotra 2015). 413

The disease mechanism of DM1 is due to DMPK RNA toxicity. Specifically, the 414

expanded DMPK mRNA, which are resistant to nuclear export, aggregate in myonuclei and form 415

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stable, double-stranded hairpin secondary structures. These CUG hairpins cause the 416

dysregulation of important RNA-binding proteins (RBPs), namely Muscleblind-like 1 (MBNL1) 417

(Chau and Kalsotra 2015). MBNL1 becomes sequestered to myonuclei due to its high affinity for 418

these hairpin foci that leads to MBNL1 loss-of-function. Dysregulation of MBNL1 therefore 419

drives alternative splicing, specifically an adult-to-fetal switch in pre-mRNA splicing patterns 420

(Chau and Kalsotra 2015). These immature isoforms are unable to meet the requirements of adult 421

skeletal muscle, the consequence of which manifests into DM1 clinical signs and symptoms. For 422

example, the myotonia of DM1 is largely attributed to the decreased expression of the muscle-423

specific chloride channel (CLC-1) (Chau and Kalsotra 2015). The loss-of-function of MBNL1 424

causes alternative splicing of CLC-1 mRNA to include exon 7a, indicative of the developmental 425

isoform. CLC-1 exon 7a, which is normally excluded from the mature transcript, contains a 426

premature termination codon resulting in the nonsense-mediated decay of the mRNA and an 427

overall reduction in functional CLC-1 protein (Chau and Kalsotra 2015). Alternative splicing 428

events in DM1 are largely attributed to the MBNL1 loss-of-function (Nakamori et al. 2013). 429

Thus, the downstream functional consequences of the DM1 mutation are ultimately due to the 430

toxic gain-of-function of DMPK mRNA within myonuclei that causes MBNL1 loss-of-function. 431

There is no cure for DM1. Anti-diabetic and -myotonic drugs, physiotherapy, assistive 432

ambulatory devices, pacemaker or implantable cardioverter defibrillator, as well as cataract 433

removal surgery, are some of the modalities currently employed to manage disease-related 434

complications. Recent pre-clinical studies employing pharmacological technologies, for example 435

ASOs or clustered regularly interspaced short palindromic repeats/Cas9-mediated editing, as 436

well as small molecules, highlight exciting advances in potential DM1 therapies (Thornton et al. 437

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2017). However, there are considerable challenges associated with these interventions that 438

currently preclude their governmental approval and availability to DM1 patients, such as their 439

unreliable targeting to affected tissues in vivo, as well as the undefined optimal frequency of 440

their administration (Havens and Hastings 2016). While these obstacles will very likely be 441

surmounted eventually, it would be advantageous to identify lifestyle-based interventions that are 442

safe, effective, and immediately deployable to improve muscle function and increase quality of 443

life in DM1 patients. 444

Exercise and DM1 445

Pioneering work from Lindeman and colleagues (1995) sought to assess the effects of 446

progressive strength training in patients with DM. The participants in this study were likely 447

individuals with DM1, being described as the authors as having the “classical, adult type”. 448

Participants trained at home three times per week using free-weights for 24 weeks targeting knee 449

extension and flexion as well as hip extension and abduction. Knee torque measures did not 450

differ between the trained group and the control, non-trained DM cohort. However, the majority 451

of patients in the trained group reported improvements in ADL. Importantly, progressive strength 452

training did not elicit signs of overwork damage as indicated by serum myoglobin levels, which 453

did not differ from the non-trained, DM control group. Subsequently, Tollbäck and colleagues 454

(1999) also utilized a resistance training paradigm that targeted the knee extensors, however their 455

participants were DM patients and the protocol consisted of exercise three times per week for 456

twelve weeks and was unilateral in nature with the opposite leg serving as the non-trained 457

control. This experimental design took into account the limited number of participants (n = 6) 458

who enrolled in the study. Here, resistance training evoked a significant improvement (+33%) in 459

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strength without magnetic resonance imaging or histological evidence of muscle damage. Thus, 460

the available evidence, albeit quite limited, suggests that resistance-type training in individuals 461

with DM1 is safe and effective at increasing strength and improving ADL. 462

To our knowledge, Wright et al. (1996) were the first to investigate endurance-type 463

training in individuals with DM. Here again unfortunately, this early work did not specify 464

whether the participants were DM1 or myotonic dystrophy type 2 (DM2) patients. The study 465

consisted of five DM participants whose training consisted of walking at 50-60% of maximum 466

HR for 15 minutes for three weeks, followed by an increased duration of 20-30 minutes for the 467

remaining nine weeks (Wright et al. 1996). Four of the five DM patients showed an 468

improvement in peak VO2 (mean of the five participants = + 9.0 ± 3.7%) on a graded exercise 469

test after twelve weeks of physical activity, while three of five demonstrated an increase in peak 470

power output (mean of the five participants = + 6.4 ± 6.1%). Training adherence was 83% and 471

low subjective scores for perceived exertion, soreness and tiredness were recorded, which 472

suggests that the training protocol was feasible, well tolerated and safe. The first examination of 473

aerobic exercise training in DM1 patients was conducted almost a decade later by Ørngreen and 474

colleagues (2005). The study recruited 17 patients, however five were excluded due to low 475

compliance. The remaining twelve participants trained on a cycle ergometer at a heart rate 476

corresponding to a work intensity of 65% VO2max for 30 minutes per session, five times/week for 477

twelve weeks. There was a 92% adherence to the training schedule in nine of twelve patients. 478

Aerobic training significantly improved VO2max by 14% and maximal workload by 11% in DM1 479

patients. Plasma creatine kinase levels did not change with increased physical activity, indicating 480

that the training protocol did not induce muscle damage. Capillary density tended to increase 481

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with training, whereas muscle fiber cross-sectional area, for both type I and IIa fibers, 482

significantly increased. In this context, it would have been interesting to determine whether 483

muscle strength also improved in response to cycle training. This, along with augmented aerobic 484

fitness, might help explain, in part, the self-reported changes in ADL, which generally improved 485

with training (Ørngreen et al. 2005). In summary, endurance-type training is well tolerated, safe, 486

and augments cardiovascular fitness and self-assessed ADL in DM1 patients. The impact of 487

aerobic training on alleviating DM1 symptoms such as myotonia, insulin resistance, and muscle 488

weakness remain to be examined. It is also worth noting here that Ørngreen and colleagues 489

(Ørngreen et al. 2005) preselected participants for their potential to complete the training regime. 490

Although many continued to train after the twelve week program, the fact that five of seventeen 491

participants withdrew from the study suggests that compliance may be a potential barrier to this 492

type of exercise prescription in DM1. 493

Manual dexterity is associated with ADL independence and social participation in DM1 494

(Kierkegaard et al. 2011). To this end, Aldehag and colleagues (2005) examined the effects of 495

hand training on strength and function in a small group of individuals with DM1. Their first 496

study consisted of five DM1 participants who competed twelve weeks of dynamic hand strength-497

endurance exercises performed three times/week. Examples of the mass wrist and finger 498

movements included flexion and extension of all fingers together except the thumb, while 499

isolated finger and thumb exercises targeted each digit individually. On average, the participants 500

completed 95% of all training sessions. Muscle force and fine motor control significantly 501

improved post-training, and a positive change in self-rated occupational performance was also 502

noted. In their subsequent investigation, the authors conducted a randomized controlled trial 503

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(RCT) employing a cross-over design with the aim of confirming and extending their previous 504

findings. Twelve weeks of dynamic hand training, three times/week, was again utilized, albeit in 505

a larger cohort of 35 DM1 patients. Ten individuals dropped out of the study, while only thirteen 506

participants exhibited acceptable (i.e., ≥ 75%) adherence. The hand training program had 507

significant, positive effects on wrist flexor force, as well as self-perception of occupational 508

performance and satisfaction of performance. Using the minimal clinically important values for 509

the Canadian Occupational Performance Measure and Assessment of Motor and Process Skills, 510

the authors observed that on an individual level, improvements were in general apparent after the 511

training period (Aldehag et al., 2013). Collectively, these studies by Aldehag et al. (2005; 2013) 512

demonstrate that this highly accessible, low-cost and -impact modality increases performance 513

and satisfaction in ADL with no detrimental effects. As the authors noted, future studies should 514

aim to advance our understanding of the personal and environmental factors in DM1 that may 515

contribute to enhance intervention adherence rates. 516

In an effort to address some of the limitations of the few, existing studies of exercise 517

training in individuals with DM1, such as short duration and small sample sizes, Brady and 518

colleagues (2014) retrospectively analyzed clinical information of 63 DM1 patients to determine 519

whether there was an association between long-term habitual physical activity and muscle 520

strength. It is important to note that, to date, this is the only study that has controlled for both age 521

and CTG repeat length between experimental groups. The data indicate that DM1 patients with 522

midrange CTG repeat size (i.e., 100-500 CTG repeats) who self-reported habitual exercise 523

participation (i.e., including all modes of physical activity, more than twice/week, for at least 1 524

full year; n = 31) outperformed their sedentary, control counterparts (n = 32) in grip strength, as 525

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well as elbow flexion and knee extension torques. Given that in a recent survey of 200 DM1 526

patients, 69% stated that they aspire to do more exercise (Gagnon et al. 2013), and that 527

resistance- and endurance-type exercise training modalities are feasible, safe, and generally well-528

received in individuals with DM1 (Kierkegaard et al. 2011), this area of research is primed to 529

advance with large RCTs designed to identify the optimal training regimes for DM1 patients 530

(Table 2). These data will in turn provide strong, evidence-based recommendations for exercise 531

as a management strategy for DM1. 532

Mechanisms of exercise biology in DM1 533

The underlying mechanisms by which chronic exercise, regardless of modality, improves 534

strength and function in DM1 are unknown. However, recent pre-clinical studies using 535

pharmacological approaches to activate AMPK, an endogenous molecule that drives exercise 536

adaptations in skeletal muscle, provide some insight. Treatment of cultured myoblasts derived 537

from DM1 patients with the anti-diabetic compound metformin (MET) normalized the 538

missplicing of six transcripts implicated in muscle biology, including the insulin receptor, 539

troponin T2, as well as the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase (Laustriat et al. 540

2015). Moreover, over 400 alternative splicing events were modulated in DM1 human 541

embryonic stem cell-derived mesodermal precursor cells treated with MET. In vivo studies 542

support and extend this cell culture-based investigation of AMPK in DM1. Indeed, 7 days of 543

daily AICAR administration to chronically activate the kinase in the human skeletal actin-long 544

repeat mouse model of DM1 was effective at either fully or partially correcting several abnormal 545

characteristics of skeletal muscle at the physiological, cellular, and molecular levels (Brockhoff 546

et al. 2017). For example, myotonia was reduced, which was caused, in part, by increased 547

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skeletal muscle CLC-1 protein content due, in turn, to a normalization of CLC-1 mRNA splicing 548

that occurred coincident with a reduction in myonuclear foci. It is reasonable to suspect therefore 549

that via an AMPK-mediated pathway, exercise training ameliorates DM1-associated myopathy, 550

in part, through correction of MBNL1 biology (Figure 3). Testing this hypothesis should be part 551

of a larger effort to identify the molecular mechanisms of exercise adaptation in DM1 (Dial et 552

al., 2018). 553

Summary and Future Perspectives 554

Many NMDs are progressive, health- and life-limiting, and have no cure. As such, these 555

disorders, including some of the most prevalent such as DMD, SMA, and DM1, bear significant 556

economic and social burdens. Recent advances in gene-based therapeutics, ASOs for example, 557

which address proximal disease mechanisms, are promising therapeutic avenues for NMDs 558

(Talbot and Tizzano 2017). Indeed, nusinersen, eteplirsen, and ataluren are all recently approved 559

gene therapy-based drugs that inspire hope for the NMD community notwithstanding the 560

biological and practical limitations inherent to each approach. Despite historical, anecdotally 561

negative connotations of exercise training in NMDs (Krivickas 2003), the scientific evidence 562

summarized in this review confirms that endurance and resistance-type exercise interventions in 563

DMD, SMA, and DM1 are safe and feasible. This declaration presumes that training principles 564

are intelligently designed so as not to exacerbate the pathology, and acknowledges that the 565

therapeutic window for exercise may be limited depending, in part, on the nature and progression 566

of the NMD. 567

Moving forward, the pressing questions that remain include identifying the optimal 568

exercise prescription (i.e., mode, frequency, intensity, duration) for each NMD, as well as to 569

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acquire the knowledge necessary to personalize the prescription for each NMD patient. 570

Furthermore, the molecular mechanisms of exercise responses and training adaptations in DMD, 571

SMA, and DM1 have yet to be resolved. Pre-clinical studies suggest that for example, AMPK, 572

p38, and CN-NFAT pathways, which drive exercise-induced plasticity in the healthy condition 573

(Egan and Zierath 2013), are also very likely involved in exercise-evoked remodeling in NMDs. 574

Further pre-clinical and clinical investigation of the molecular mechanisms of exercise in DMD, 575

SMA, and DM1 is important because it will expand our understanding of the biology of these 576

most prevalent NMDs, as well as assist in identifying novel therapeutic targets for future pursuit. 577

In all, concerted efforts by those in the NMD community will continue to be required in order to 578

advance the implementation of exercise prescription as an effective therapeutic modality, as well 579

as exercise as a strategy for basic therapeutic discovery, for individuals with compromised 580

neuromuscular systems. 581

582

Acknowledgments 583

Work in the authors’ laboratory is funded by the Canadian Institutes of Health Research 584

(CIHR), the Natural Sciences and Engineering Research Council of Canada, and the Canada 585

Research Chair (CRC) program. VL is the Tier 2 CRC in Neuromuscular Plasticity in Health and 586

Disease. AM is the recipient of a CIHR Canada Graduate Scholarship. 587

588

Conflict of Interest Statement 589

The authors have no conflicts of interest to report. 590

591

592

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Phys. Med. Rehabil. 77(1): 64–69. W.B. Saunders. doi:10.1016/S0003-9993(96)90222-1. 776

777

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Figure Legends 778

Figure 1. Potential cellular pathways in skeletal muscle for exercise adaptation in 779

Duchenne muscular dystrophy. Pre-clinical studies in dystrophic mdx mice provide 780

some indication of the mechanisms that drive exercise-induced skeletal muscle plasticity 781

in DMD. Acute exercise upregulates AMPK and p38 activation status, coincident with 782

the elevation of SIRT1, PPARδ, and PGC-1α transcripts in mdx mouse muscle (Ljubicic 783

2012). Complementary investigations capitalize on the availability of pharmacological 784

compounds, such as AICAR or heparin, which stimulate discrete molecules that are also 785

activated by physical activity, or utilize genetic strategies to induce the expression and/or 786

activity of exercise-responsive proteins, for example transgenic overexpression of PGC-787

1α or HSPs. Downstream events, including the stimulation of corrective autophagic 788

signalling, promotion of the slow, oxidative myogenic program, and the transcriptional 789

and post-transcriptional increase in utrophin expression, contribute to structural and 790

functional improvements in dystrophic skeletal muscle. Solid lines indicate established 791

connections between events. Dashed lines refer to potential linkages between steps. 792

Question mark indicates alternative, undiscovered pathways and/or mechanisms. Arrows 793

illustrate activation, while horizontal line indicates p38-mediated inhibition of KSRP 794

function. 795

796

Figure 2. Putative mechanisms of exercise-induced neuromuscular plasticity in 797

spinal muscular atrophy. Studies of physical activity or small molecules in SMA mice 798

demonstrate possible pathways of exercise adaptation. Activation of upstream molecules, 799

for example AMPK, CaMKII, and p38, may initiate a signalling cascade that results in an 800

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38

increase in FL-SMN expression in the neuromuscular system. Exercise-evoked 801

alterations in skeletal muscle and αMNs might occur in both SMN-dependent and SMN-802

independent fashion. These beneficial adaptations result in enhanced healthspan and 803

lifespan of mice with SMA. Dashed lines refer to potential linkages between steps. 804

Question marks indicate alternative, undiscovered pathways and/or mechanisms. Arrows 805

illustrate activation. 806

807

Figure 3. Mechanisms that may drive skeletal muscle exercise adaptations in 808

myotonic dystrophy type 1. Potential mechanisms of exercise-induced muscle plasticity 809

in DM1 are largely unknown. Pharmacological activation of AMPK, which is also well 810

known to be robustly and reproducibly stimulated by exercise, causes the normalization 811

of alternative splicing in pre-clinical models of DM1 in vivo and in vitro. This is likely 812

due to the release of MBNL1 from myonuclear foci, as well as due to other undefined 813

mechanisms. The correction of mRNA processing is associated with the upregulated 814

expression and function of encoded proteins, and improvements in skeletal muscle 815

structure and clinical function. Dashed lines refer to potential linkages between steps. 816

Question marks indicate alternative, undiscovered pathways and/or mechanisms. Arrows 817

illustrate activation. 818

819

820

821

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Table 1: Summary of exercise studies in participants with SMA Exercise

mode

Participant

cohort size SMA type Exercise protocol Safety Adherence Effects Reference

Arm cycle

ergometer

7 Type II 12 week training

program; 3x per week;

30 minute sessions at

60% MHR

Exercise training was

well tolerated; no

reports of myalgia

Two participants

dropped out

Increase in cycling distance

and duration at weeks 6 and 12

compared to pre-exercise

values; no change in peripheral

blood SMN expression

Bora et al.,

2018

Leg cycle

ergometer

8 Type III 12 week training

program; 2-4x per week;

30 minute sessions at

60-75% VO2max

No training-induced

increases in plasma

creatine kinase

Two participants

dropped out

27% increase in VO2max; 3

patients reported improved

muscle strength, 2 reported

increased levels of activity, 6

reported increased fatigue

Madsen et al.,

2015

Leg cycle

ergometer;

resistance

exercise

14 Type III 6 month training


whole body resistance

training, 3x per week;

30 minute sessions; 60-

80% 1RM

Exercise was well

tolerated; no adverse

events reported

12 participants

completed the

exercise training

protocol

~5% increase in VO2max; no

change in MMT; no change in

6MWT or clinical measures of

motor function

Montes et al.,

2015

Resistance

exercise

9 Type II &

type III

12 week training


progressive resistance

training

Training sessions

were 99.5% pain-

free; no adverse

events reported

High participant

adherence

(90.4%)

Increased muscle strength

revealed by MMT;

improvement in MHFMSE

score

Lewelt et al.,

2015

Resistance

exercise

3 Not stated -

likely to be

mild SMA

9 week training



training from 40-70%

MVC; single arm and

bilateral leg

Muscle biopsy and

computerized

tomography revealed

no training-induced

muscle damage

All participants

completed

training

Improved dynamic strength in

the arms and legs; greater

isokinetic torque generation,

and enhanced elbow flexor

contractile properties

McCartney et

al., 1988

Resistance

exercise

3 Not stated -

likely to be

type III/IV

12 month training



training

Not stated Participants did

not experience

overwork

weakness.

Elbow flexion was not reported

due to the lack of initial

strength; maximal knee

extension force increased

~100%

Milner-Brown

and Miller 1988

6MWT = 6 minute walk test; MHFMSE = Modified Hammersmith Functional Motor Scale-Extend; MHR = maximal heart rate; MMT = Manual Muscle Testing;

MVC = maximal voluntary contraction; RM = repetition max; SMA = spinal muscular atrophy; SMN = survival motor neuron.

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Table 2: Summary of exercise studies with DM1 participants

Exercise

mode

Participant

cohort size DM type Exercise Protocol Safety Adherence Effects Reference

Habitual

physical

activity

63 DM1 Retrospective study;

participants were

habitually active > 2x

per week

Not stated Not stated Mean handgrip strength, knee

extension and elbow flexion

torques higher in active cohort

versus sedentary

Brady, MacNeil,

Tarnopolsky,

2014

Hand

resistance

training

35 DM1 12 week training

program; 3x per week

Not stated Ten participants

dropped out; 13

participants had

acceptable

adherence (>

75%)

Isometric wrist flexor force

improved post-training; no

change in handgrip force;

satisfaction and change in self-

perception of occupational

performance increased

Aldehag et al.,

2013

Resistance

and

endurance

exercise

35 (n = 17

trained; n =

18

sedentary)

DM1 14 week training


60 minute group-

training programme at

60% MHR

One participant

demonstrated

abnormal ECG,

otherwise no adverse

events reported

11/18 participants

≥ 75% attendance

Mean 6MWT increased (P >

0.05) in the trained group by

9m

Kierkegaard et

al., 2011

Leg cycle-

ergometer



intensity of 65% of

VO2max; 35 minute

sessions

Plasma creatine

kinase was

unchanged

76% adherence to

training program

Training improved VO2max by

14%, maximal workload by

11%; increased type I and IIa

fibre cross sectional area; no

change in capillary density

Ørngreen et al.,

2005

Hand

resistance

training


program; 3x per week

Not stated Not stated Increase in muscle force of

wrist and finger extensors and

flexors of the dominant hand;

no difference in grip force;

improved fine motor control in

both hands; participants rated

high occupational performance

and satisfaction

Aldehag et al.,

2005

Resistance

training

9 DM 12 week training



training with 3 x 10

repetitions 80% 1RM

No histological

evidence of increased

muscle damage with

training

6/9 participants

completed

training program

1 RM increased post-training;

no change in peak isokinetic

torque; no difference in muscle

cross sectional area; no effect

on fiber type distribution

Tollbäck et al.,

1999

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Aerobic

training

5 DM 12 week training


15-30 minute session

walking at 50-60% of

MHR

Low rating of

perceive exertion

83% adherence Decrease in submaximal heart

rate and systolic blood

pressure; four of the five DM

patients showed an

improvement in peak VO2

Wright et al.,

1996

Resistance

training

33 (n = 19

trained; n =

14

sedentary)

DM 24 week training



training; 60–80% 1RM

No change in serum

myoglobin

18/19 participants

completed

training program

No training effect observed in

strength measures and

endurance tests; improvement

in functional metrics

Lindeman et al.,

1995

Resistance

exercise

4 DM 20 month training



training

Not stated All participants

completed the

training program

Maximal elbow flexion

strength unchanged; maximal

knee extension force increased

100%

Milner-Brown

and Miller 1988

6MWT = 6 minute walk test; DM = myotonic dystrophy; DM1 = myotonic dystrophy type 1; ECG = electrocardiogram; MHR = maximal heart rate; RM =

repetition max.

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Exercise + DMD

• Decreased myopathy • Enhanced sarcolemma structural integrity

• Increased force production

KSRP ?

AMPK SIRT1 PPARδ CN p38 HSPs

Slower more oxidative characteristics

PGC-1α NFAT

Increased utrophin

expression

Mitochondrial biogenesis

Angiogenesis Attenuated Ca2+ dysregulation &

inflammation

Corrective autophagy

mRNA stabilization

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Exercise + SMA

Increased FL-SMN mRNA

Increased FL-SMN protein

p38

HuR

mRNA stabilization

CAMKII

CREB

AKT

Increased

transcription

Improved NMJ biology Preservation of αMN number

AMPK

? ?

• Absence of muscle damage • Improved muscle strength • Enhanced motor function

• Prolonged survival

FL FL FL

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Decreased CUG foci MBNL1 liberation

I

AMPK

Corrective splicing

Exercise + DM1

Enhanced expression of ClC-1 proteins

I I

?

?

• Healthy muscle contraction and relaxation

• Diminished myopathy

ClC-1

INSR Troponin T2

SERCA

7 7a 8

4 5 6 10 11 12

21 22 23

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Exercise Biology of Neuromuscular Disorders...83 readers are directed to excellent papers on this...

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