Diseases of Skeletal Muscle

By: Shefaa’ Al qa’qa’

• Skeletal muscle has unique structural, cellular, and molecular characteristics and accordingly unique patterns of injury and repair.

• Myoblasts: precursor cells • Myofibers (muscle fibers): mature cells (myocytes), arranged in

fascicles • Satellite cells: stem cells • Myofibers are of two main types, type I and type II , which are

admixed in a checkerboard pattern in normal skeletal muscle. Fiber type is determined by signals received from innervating motor neurons and, as a result, all fibers that are part of a motor unit are of the same type.

• Diseases of Skeletal Muscle:

- Skeletal muscle atrophy

- Inflammatory Myopathies

- Toxic Myopathies

- Inherited Diseases of Skeletal Muscle (Congenital Myopathies, Muscular dystrophies)

Skeletal muscle atrophy

• Skeletal muscle atrophy is a common feature of many disorders.

• Loss of innervation, disuse, cachexia, old age, and primary myopathies can all produce muscle atrophy and, if the atrophy is severe, loss of muscle mass.

• Certain patterns of atrophy are suggestive of specific

underlying etiologies: - grouped atrophy are seen in neurogenic disease. - Perifascicular atrophy is seen in dermatomyositis. - Type II fiber atrophy with sparing of type I fibers is seen with prolonged corticosteroid therapy or disuse.

• Disorders impacting skeletal muscle may do so by:

- disrupting muscle innervation (neurogenic injury)

- damaging myofibers directly (myopathic injury)

• Neurogenic injuries lead to fiber type grouping and grouped atrophy , both of which stem from the disruption of muscle innervation. The key to understanding these abnormalities is to recognize that muscle fiber type is determined by the innervating motor neuron and can switch if the innervating motor neuron changes from one type to the other. Following denervation, myofibers undergo atrophy, often assuming a flattened, angulated shape. Reinnervation restores fiber size and shape, but may make a denervated myofiber part of a different motor unit and that may lead to a switch in fiber type. In the face of ongoing axonal or neuronal damage and drop out, residual motor axons may innervate increasingly larger numbers of myofibers, leading to enlargement of motor units, each comprised of a single type of muscle fiber (fiber type grouping). These large motor units are also susceptible to grouped atrophy if the innervating axon is damaged.

• myopathic injury are associated with a distinct set of morphologic changes that include the following:

- Segmental myofiber degeneration and regeneration is seen when only part of a myofiber undergoes necrosis. - Degeneration is associated with release of cytoplasmic

enzymes into the blood such as creatine kinase, making these useful markers of muscle damage.

- The sarcomeres and other components of the damaged myofiber segment are removed by macrophages in a process termed myophagocytosis.

- Myofiber hypertrophy - Cytoplasmic inclusions

• Regenerating myofibers are rich in RNA and therefore blue (basophilic) in hematoxylin and eosin stained sections. They have enlarged nuclei with prominent nucleoli that are often randomly distributed in the cytoplasm, instead of being in their normal subsarcolemmal location.

Fusion of activated satellite cells to damaged myofibers is an important step for regeneration. Regeneration can restore muscle to normal following an acute, transient injury, but in chronic disease states regeneration often fails to keep pace with damage. In this setting, muscles often show endomysial fibrosis (collagen deposition), dropout of myofibers, and fatty replacement.

Inflammatory Myopathies

• polymyositis, dermatomyositis, and inclusion

body myositis have been considered the three main primary inflammatory myopathies.

Other immune-mediated disorders, such as systemic lupus erythematosus, systemic sclerosis, and sarcoidosis, as well as certain infectious agents, can also cause myositis.

Dermatomyositis

- Dermatomyositis is a systemic autoimmune disease that typically presents with proximal muscle weakness and skin changes.

- Dermatomyositis is an immunologic disease in which damage to small blood vessels contributes to muscle injury. The vasculopathic changes can be seen as telangiectasias (dilated capillary loops) in the nail folds, eyelids, and gums, and as dropout of capillary vessels in skeletal muscle

• Certain autoantibodies tend to be associated with specific clinical features:

- Anti-Mi2 antibodies

- Anti-Jo1 antibodies

- Anti-P155/P140 antibodies

• MORPHOLOGY:

Muscle biopsies of affected patients show infiltrates of mononuclear inflammatory cells that tend to be most pronounced in the perimysial connective tissue and around blood vessels. Sometimes there is a distinctive pattern in which myofiber atrophy is accentuated at the edges of the fascicles perifascicular atrophy.

Immunohistochemical studies may identify an infiltrate rich in CD4+ T-helper cells and the deposition of C5b-9 in capillary vessels.

• Clinical Features: - Muscle weakness is slow in onset, symmetric, and often accompanied by myalgias. It typically affects the proximal muscles first. As a result, tasks such as getting up from a chair and climbing steps become increasingly difficult. Fine movements controlled by distal muscles are affected only late in the disease. Associated myopathic changes on electrophysiologic studies and elevation in serum creatine kinase levels are reflective of muscle damage. - Various rashes are described in dermatomyositis, but the most characteristic ones are a lilac colored discoloration of the upper eyelids (heliotrope rash) associated with periorbital edema (Fig. 27-8A) and a scaling erythematous eruption or dusky red patches over the knuckles, elbows, and knees (Gottron papules). - Dysphagia resulting from involvement of oropharyngeal and esophageal muscles occurs in one third of the affected individuals, - and another 10% of patients have interstitial lung disease, which can sometimes be rapidly progressive and lead to death. - Cardiac involvement is common, but rarely leads to cardiac failure.

• Juvenile and adult forms are recognized.

- The average age of onset of juvenile dermatomyositis is 7 years, whereas adult cases tend to present from the fourth to sixth decade of life.

- From 15% to 24% of adult patients have an associated malignancy, and in such patients dermatomyositis may be viewed as a paraneoplastic disorder.

- the overall prognosis is better in children than in adults (childhood disease is less likely to be associated myositis specific antibodies, cardiac involvement, interstitial lung disease, or an underlying malignancy)

Polymyositis

• Polymyositis is an adult-onset inflammatory myopathy that shares myalgia and weakness with dermatomyositis but lacks its distinctive cutaneous features.

• As in dermatomyositis, patients typically develop symmetric proximal muscle involvement, and there may be inflammatory involvement of the heart and the lungs, as well as similar autoantibodies.

• Pathogenesis:

The pathogenesis of polymyositis is uncertain, but it is believed to have an immunologic basis. CD8- positive cytotoxic T cells are a prominent part of the inflammatory infiltrate in affected muscle, and it is hypothesized that these cells are the mediators of tissue damage.

Unlike dermatomyositis, vascular injury is not believed to have a major role in polymyositis.

• MORPHOLOGY: - Mononuclear inflammatory cell infiltrates are present, but in contrast to dermatomyositis, these are usually endomysial in location. - myofibers with otherwise normal morphology appear to be invaded by mononuclear inflammatory cells. - Degenerating necrotic, regenerating, and atrophic myofibers are typically found in a random or patchy distribution. The perifascicular pattern of atrophy that is characteristic of dermatomyositis is absent.

Inclusion body myositis

• Inclusion body myositis is a disease of late adulthood that typically affects patients older than 50 years and is the most common inflammatory myopathy in patients older than age 65 years.

• Most affected individuals present with slowly progressive muscle weakness that tends to be most severe in the quadriceps and the distal upper extremity muscles.

• Dysphagia from esophageal and pharyngeal muscle involvement is not uncommon.

• Laboratory studies usually show modestly elevated creatine kinase levels.

• most myositis-associated autoantibodies are absent, although an antibody to cN1A has recently been described.

• MORPHOLOGY: Inclusion body myositis has a number of features that are similar to those found in polymyositis, including: - Patchy often endomysial mononuclear inflammatory cell infiltrates rich in CD8+ T-cells - Focal invasion of normal appearing myofibers by inflammatory cells - Admixed degenerating and regenerating myofibers

Other associated changes, however, are more typical or even specific for inclusion body myositis, as follows: - Abnormal cytoplasmic inclusions described as “rimmed vacuoles” - Tubolofilamentous inclusions in myofibers, seen by electron microscopiy - Cytoplasmic inclusions containing proteins typically associated with neurodegenerative diseases, like beta-amyloid, TDP-43, and ubiquitin - Endomysial fibrosis and fatty replacement, reflective of a chronic disease course.

• Whether inclusion body myositis is indeed an inflammatory condition or a degenerative process with secondary inflammatory changes remains an unresolved question.

Treatment of Inflammatory Myopathies

• The prognosis for patients with dermatomyositis and polymyositis was poor before the use of corticosteroids, with mortality rates as high as 50% or more.

• Corticosteroids remain the first-line of treatment for polymyositis and dermatomyositis.

• Immunosuppressive drugs are used in steroid-resistant disease or as steroid-sparing agents and include azathioprine and methotrexate.

• Inclusion body myositis usually responds poorly to steroids or immunosuppressive therapies, another feature that argues against an inflammatory or immune origin for this disorder.

Muscular Dystrophies

• Muscular dystrophies include several inherited disorders of skeletal muscle that have in common progressive muscle damage that typically manifests itself between childhood and adulthood.

X-Linked Muscular Dystrophy with Dystrophin Mutation/

Duchenne and Becker Muscular Dystrophy

• The most common muscular dystrophies are X-linked and stem from mutations that disrupt the function of a large structural protein called dystrophin.

• The most common early onset form is referred to as Duchenne muscular dystrophy. It has an incidence of 1 per 3500 live male births and has a severe progressive phenotype.

• Becker muscular dystrophy is a second relatively common dystrophinopathy that is characterized by later disease onset and a milder phenotype.

• As with many X-linked diseases, female carriers of dystrophin mutations may be mildly symptomatic due to unfavorable X-chromosome inactivation.

• Pathogenesis:

- Duchenne and Becker muscular dystrophy are caused by loss-of-function mutations in the dystrophin gene on the X chromosome.

- The encoded protein, dystrophin, is a key component of the dystrophin glycoprotein complex (DGC).

• dystrophin is thought to provide mechanical stability to the myofiber and its cell membrane during muscle contraction. Defects in the complex may lead to small membrane tears that permit influx of calcium, triggering events that result in myofiber degeneration.

• In addition to its mechanical function, dystrophin may have a role in signaling pathways.

• Duchenne muscular dystrophy is typically associated with deletions or frame shift mutations that result in total absence of dystrophin.

• In contrast, the mutations in Becker muscular dystrophy typically permit the synthesis of a truncated version of dystrophin, which presumably retains some function.

• MORPHOLOGY:

- The changes in Duchenne and Becker muscular dystrophy are similar, but differ in degree.

- Muscle biopsies in young boys show ongoing damage in the form of segmental myofiber degeneration and regeneration associated with an admixture of atrophic myofibers.

• As the disease progresses, muscle tissue is replaced by collagen and fat cells (“fatty replacement” or “fatty infiltration”). The remaining myofibers at this point in the course show prominent variation in size, from small atrophic fibers to large hypertrophied fibers. This remodeling distorts the fascicular architecture of the muscle, which becomes markedly abnormal over time.

• Immunohistochemical studies for dystrophin show absence of the normal sarcolemmal staining pattern in Duchenne muscular dystrophin and reduced staining in Becker muscular dystrophy.

• Clinical Features: - Boys with Duchenne muscular dystrophy are normal at birth. Very early motor milestones are met, but walking is often delayed. The first indications of muscle weakness are clumsiness and inability to keep up with peers. - Weakness begins in the pelvic girdle muscles and then extends to the shoulder girdle. - Enlargement of the muscles of the lower leg associated with

weakness, termed pseudohypertrophy, is often present. - The mean age of wheel chair dependence is around 9.5 years. - Patients develop joint contractures, scoliosis, worsening respiratory

reserve, and sleep hypoventilation.

• Dystrophin is also expressed in the heart and the central nervous system, hence both are affected.

• Dystrophin deficiency in cardiac muscle often leads to the development of cardiomyopathy and arrhythmias, particularly in older patients.

• Cognitive impairment, presumably due to a functional role for dystrophin in the brain, is also common and sometimes produces frank mental retardation.

• Despite supportive care, the mean age of death for patients with Duchenne muscular dystrophy is 25 to 30 years of age, with most patients succumbing to respiratory insufficiency pulmonary infection, or heart failure.

• In contrast, Becker muscular dystrophy presents in later childhood, adolescence or adult life. Its course is more slowly progressive often with a near normal life expectancy.

• Serum creatine kinase is markedly elevated during the first decade of life due to ongoing muscle damage, and then falls as the disease progresses and muscle mass is lost.

• The presence of a dystrophin mutation can be confirmed by genetic studies.

• Treatment of patients with dystrophinopathies is challenging. Current treatment consists primarily of supportive care. Definitive therapy requires restoration of dystrophin levels in skeletal and cardiac muscle fibers.

• Gene therapy (introduction of a normal dystrophin gene) is being investigated, but gene delivery to skeletal muscle cells remains a daunting hurdle.