Does Pharmacological Exercise Mimetics Exist?
Transcript of Does Pharmacological Exercise Mimetics Exist?
Does Pharmacological Exercise Mimetics Exist?
Hokkaido University Graduate School of Medicine
Shintaro Kinugawa
100
0
50
25
0
9 15
75
3 6 12
Su
rviv
al
rate
(%
)
Follow up (Months)
Peak Oxygen Uptake (VO2)
(mL/kg/min) >18
>14 ≦18 >10 ≦14
≦10*
Peak oxygen uptake and prognosis in patients with heart failure (HF)
Mancini DM, et al. Circulation 1991; 83: 778-786
Factors regulating exercise capacity
VCO2
VO2
Lung Heart
Blood
Pulmonary circulation Peripheral circulation
Skeletal muscle
Mitochondria Expiration
Inspiration
O2 transport
CO2 transport
CO2 production
O2 consumption
Reserve capacity
Large Small
0
1
2
3
4
5
Rest Submax Max
*
*
Control Dobutamine
0
20
40
60
80
100
Rest Submax Max
*
* *
Rest Submax Max
0
500
Rest Submax Max
1000
0
10
20
30
40
50
Wilson JR, et al. Am J Cardiol. 1984; 53: 1308-15
Dobutamine does not increase exercise capacity
Leg
blo
od
flo
w (
L/m
in)
O2 e
xtr
act
ion
(%
)
VO
2 (
mL
/min
)
La
ctate
(m
g/d
L)
Morphology Histology Biochemistry Others
Muscle wasting
Muscle fiber atrophy
(IIb)
Type I fibers
Type II fibers
Shift from type IIa to
IIb
Oxidative enzymes
Glycolytic enzymes
Impaired energy
metabolism
Ergoreflex
Capillary density Shift from MHC1 to
MHC2
Mitochondrial volume eNOS
Apoptosis
Skeletal muscle abnormalities in HF
Okita K, et al. Circ J 2013; 77: 293-300
Skeletal muscle abnormalities are largely associated with the limited exercise
capacity in patients with HF and are the target of exercise therapy.
Modified, Piepoli MF. BMJ 2004; 328: 189
Su
rviv
al
rate
(%
)
Follow up (days)
70
80
90
100
0 100 200 300 400 500 600 700
Training
Control
Aerobic exercise training improves survival rate
in patients with HF
(ExTraMATCH)
1. Improve exercise capacity (peak VO2, AT)
2. Minor change in cardiac function (LV systolic function and
remodeling)
3. Improve endothelial function (Coronary and peripheral
circulation)
4. Improve ventilation
5. Improve autonomic nerves function
6. Improve skeletal muscle abnormalities
Effects of exercise therapy for heart failure
The greatest effect is to improve skeletal
muscle abnormalities.
Treatment targeting skeletal muscle abnormalities
Skeletal muscle abnormalities play an important role in the
pathogenesis of HF. However, no therapy targeting skeletal
muscle abnormalities has been developed. Developing new drug
therapy may be useful for treatment of patients with severe HF
who can’t perform aerobic exercise.
We focused on myokine secreted from skeletal muscle and
performed studies.
Pedersen BK, et al. Nat Rev Endocrinol 2012; 8: 457-65
Skeletal muscle is a huge endocrine organ
Control Caffeine
kDa
30
25
20
15
10
Mass
spectrometry
MWM
40
60
80 100 150
C2C12 myotubes
(mouse skeletal muscle)
Medium
Caffeine
(skeletal muscle
contraction)
Silver stain MW
Cultured medium
Without caffeine With caffeine
Name Cover
(%)
MASCOT
score Name
Cover
(%)
MASCOT
score
MIF 21 317 MIF 21 115
VEGF 6 38 VEGF 14 89
SPARC 5 36 BDNF 8 71
FSTL 3 44 FSTL 3 30
Search for proteins secreted by skeletal muscle contraction
BD
NF
/to
tal p
rote
in
(Ra
tio
to
ga
str
o)
BDNF
Gastro Soleus
0
0.5
1
1.5
2
Gastro Soleus
CBB
staining
SDH
* * *
Type II Type I
* *
* * *
* *
BDNF
Type I Type II
BDNF
Soleus
Gastrocnemius
*
BDNF is preferentially present in the slow twitch fiber
AMP
ATP
Transcription
Nucleus
β-oxidation
β-HAD
Mitochondrion TCA cycle NADH
FADH2
ATP
CO2
NAD+
FAD
ADP+Pi
Acetyl-CoA
CaMKK
CaMK
PGC1α
AMPKα SIRT1
SIRT3
NAD+
NADH
ROS
NO
p38MAPK
ATP
Electron transport chain
I II III IV
V
Cyt c
F0
F1
H+ H+ H+ ADP
+Pi
NA
DH
N
AD
+
Intermembrane
space
Matrix
Signal regulating mitochondrial biogenesis
Kinugawa et al. Int Heart J 2015; 56:475-84
TrKBR
BDNF rhBDNF BDNF KO mice
Work
(J)
0
5
10
15
20
25
30
35
SED+
vehicle
SED+
rhBDNF
ET+
vehicle
* *
Peak
VO
2 (
mL
/kg/m
in)
100
110
120
130
140
150
160
170
180
SED+
vehicle
SED+
rhBDNF
ET+
vehicle
* *
Ru
n d
ista
nce (
m)
Ru
n t
ime
(sec
)
0
100
200
300
400
500
600
700
800
SED+
vehicle
SED+
rhBDNF
ET+
vehicle
* *
0
500
1000
1500
2000
2500
SED+
vehicle
SED+
rhBDNF
ET+
vehicle
* *
BDNF mimics exercise training
rhBDNF + =
What a wonderful thing if this happen!!
p-AMPK
AMPK
0.0
0.5
1.0
1.5
2.0
SED+
vehicle
SED+
rhBDNF
ET+
vehicle
mtD
NA
(Ra
tio
to
SE
D+
veh
icle
)
P-A
MP
K/A
MP
K
* *
PGC-1
GAPDH
0.0
0.1
0.2
0.3
0.4
SED+
vehicle
SED+
rhBDNF
ET+
vehicle
PG
C-1
/GA
PD
H
*
0.0
0.1
0.2
0.3
0.4
SED+
vehicle
SED+
rhBDNF
ET+
vehicle
* *
*
Signaling regulating mitochondrial function
rhBDNF
p-AMPK Mitochondrial
function
Exercise
capacity
Exercise Training
BDNF
0
50
100
150
200
250
WT BDNF KOBDNF KO
+AICAR
CS
acti
vit
y
(mM
/min
/mg p
rote
in)
BDNF
GAPDH
P-AMPK
AMPK
BD
NF
/GA
PD
H
P-A
MP
K/A
MP
K
0.0
0.2
0.4
0.6
0.8
1.0
WT BDNF KOBDNF KO
+AICAR
†
0.0
0.2
0.4
0.6
0.8
1.0
WT BDNF KOBDNF KO
+AICAR
* * *
†
*
Pea
k V
O2,
mL
/kg
/min
Wo
rk,
J
100
120
140
160
180
WT BDNF KOBDNF KO
+AICAR
0
10
20
30
WT BDNF KOBDNF KO
+AICAR
†
* †
*
Effects of AMPK activator in BDNF KO mice
BDNF KO mice
p-AMPK
AICAR(AMPK activator) +
Mitochondrial
function
Exercise
capacity
0
0.2
0.4
0.6
0.8
1
1.2
Sham+vehicle
MI+vehicle
MI+rhBDNF
Sham+
vehicle
MI+
vehicle
BDNF
GAPDH
MI+
rhBDN
F
BD
NF
/GA
PD
H †
*
0
2
4
6
8
10
12
Sham+vehicle
MI+vehicle
MI+rhBDNF
Ser
um
BD
NF
(ng
/ml)
n.d. n.d.
BDNF expression is decreased in the skeletal muscle from
mice with HF after myocardial infarction
4wk
Intervention
Sham
MI
Sham+vehicle
MI+vehicle
MI+rhBDNF
Ope 2wk
Observation
Matsumoto J, et al. Circulation 2018; 138:2064-6
0
20
40
60
80
100
120
140
160
180
Sham+vehicle
MI+vehicle
MI+rhBDNF
Ph
ysi
cal
acti
vit
y (
cou
nt/
day
)
0
5
10
15
20
25
30
35
Sham+vehicle
MI+vehicle
MI+rhBDNF
0
5
10
15
20
25
30
Sham+vehicle
MI+vehicle
MI+rhBDNF
0
100
200
300
400
500
600
Sham+vehicle
MI+vehicle
MI+rhBDNF
* * †
*
* †
* * †
* †
0
1000
2000
3000
4000
5000
6000
Sham+vehicle
MI+vehicle
MI+rhBDNF
NS
Tota
l w
ork
(J)
Pea
k V
O2 (m
L/k
g/m
in)
To
tal
run
nin
g t
ime
(min
)
Tota
l ru
nnin
g d
ista
nce
(m
)
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
Sham+vehicle
MI+vehicle
MI+rhBDNF
Lac
tate
/wo
rk (
mm
ol/
L/J
) *
†
BDNF improves exercise capacity in HF mice
Matsumoto J, et al. Circulation 2018; 138:2064-6
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Sham+vehicle
MI+vehicle
MI+rhBDNF
pA
MP
Kα/AMPKα
*
†
PGC1α
/GA
PD
H
0
0.2
0.4
0.6
0.8
1
1.2
Sham+vehicle
MI+vehicle
MI+rhBDNF
*
† Sham+ vehicle
MI+ vehicle
MI+ rhBDNF
pAMPKα
PGC1α
GAPDH
AMPKα
BDNF activates AMPKα-PGC1α signal
in the skeletal muscle
0.0
0.2
0.4
0.6
0.8
1.0
1.2
CILeak
CIOXPHOS
CI+IIOXPHOS
CI+IIETS
CIIETS
Sham+vehicle
MI+vehicle
MI+rhBDNF
* * *
†
*
†
†
*
O2 f
lux
(rat
io t
o C
I+II
ET
SS
ham
+veh
icle)
P=0.08
P=0.13
BDNF improves mitochondrial respiration
in the skeletal muscle
Matsumoto J, et al. Circulation 2018; 138:2064-6
30
40
20
10
0
Peak VO2 (mL/kg/min)
0
r=0.53, P<0.001
10 20 30 40 50
Fukushima A, et al. Int J Cardiol 2013; 168: e142-4
40
30
20
10
0
P<0.001
Ser
um
BD
NF
(n
g/m
L)
Control HF
Ser
um
BD
NF
(n
g/m
L)
Control
HF
BDNF and exercise capacity in patients with HF
Fukushima A, et al. J Cardiac Fail 2015; 21: 300-6
0
0.2
0.4
0.6
0.8
1.0
0 5 10 15 20 25 30
BDNF≧17.4 ng/mL
(n=37)
BDNF<17.4 ng/mL
(n=21)
Log-rank test
P=0.001
Ev
ent-
free
rate
Months
BDNF is an independent predictor for clinical events
Conclusion
BDNF may be a new treatment aiming
at improvement in exercise capacity and
targeting skeletal muscle.