Exercise Intolerance in Heart Failure:

Significance of Skeletal Muscle Abnormalities

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

Sleep disordered breathing

Metabolic disorder

Skeletal muscle

abnormalities

Endothelial dysfunction Immunological disorder

CKD

Anemia

HF

Cardiac dysfunction

Activation of neurohumoral factors

Depression

HF is a systemic disorder

Exercise capacity and pathology of HF

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

Exercise therapy is a highly ideal

treatment for HF and is a standard of care.

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)

Leg bicycle

ergometer

Does heart regulate peak whole body exercise capacity?

Jondeau G, et al. Circulation 1992; 101: 219S-222S

0

1

2

3

<15 >15 Normal

Increase in VO2

Peak VO2

*

* (ml/

kg/m

in)

Arm bicycle

ergometer

The heart is not reaching the limit

at the limit of exercise (peak VO2) as

severe heart failure

Added arm bicycle ergometer

when AT is exceeded

Skeletal muscle is impaired in patients with HF

Drexler H, et al. Circulation

1992; 85: 1751-9

Decreased mitochondrial

enzyme (cyto C)

HF

Control

Sabbah HN, et al. Circulation

1993; 87: 1729-37

HF

Control

Decreased slow twitch

fiber and capillary

Skeletal muscle metabolism

Okita K, et al. Circulation 1998;

98: 1886-91

Impaired metabolism

independent on blood flow

Energy metabolism in the skeletal muscle during exercise

Peak VO2

Mitochondria

O2 H2O ATP

Skeletal

muscle cells

Fatty acid

Cr + Pi

β-oxidation

Muscle contraction

1H-MRS

Exercise capaciy

31P-MRS

PCr, phosphocreatine; Pi, inorganic phosphate; Cr, creatine; IMCL, intramyocellular lipid

PCr IMCL

in HF patients

Whole body

MR system Rapid

inflator

What is happening in skeletal muscle during whole body exercise?

5 0 -5 -10 - 1 5 -20 5 0 -5 -10 - 1 5 -20

pH=7.02pH=7.02

pH=6.63pH=6.63 pH=6.42pH=6.42

pH=7.07pH=7.07

chemical shift (ppm)chemical shift (ppm) chemical shift (ppm)chemical shift (ppm)

PCrPCrPCrPCr

PiPiPiPi

PiPi PiPi

ATPATP

αα ββγγ

ATPATP

αα ββγγ

PCrPCr PCrPCr

RestRest

Peak

Exercise

Peak

Exercise

Normal subjectNormal subject CHF patientCHF patient

(Okita K. Circulation, 1998)(Okita K. Circulation, 1998)

PCr depletion at peak exercise

Okita K, et al. Circulation 1998; 98: 1886-91

RestRestRestRest

1010 1515 2020 2525 3030 3535 40400.00.0

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

0.60.6

0.70.7

0.80.8

0.90.9

1.01.0

006.26.2

6.36.3

6.46.4

6.56.5

6.66.6

6.76.7

6.86.8

6.96.9

7.07.0

7.17.1

7.27.2

1010 1515 2020 2525 3030 3535 404000

**

PhosphocreatinePhosphocreatine Muscle pHMuscle pH

CHFCHF

ControlsControls

CHFCHF

ControlsControls

Vo2 (ml/min/kg)Vo

2 (ml/min/kg) Vo

2 (ml/min/kg -)Vo

2 (ml/min/kg -)

Muscle metabolism during systemic exerciseMuscle metabolism during systemic exercise

*p<0.05

Fig 2-2. Muscle metabolism during maximal bicycle exercise. The phosphocreatine was nearly depleted at peak exercise in both groups. Muscle pH was more severely decreased in patients than in controls ..

Impaired skeletal muscle metabolism

Decreases in phosphocreatine and pH are larger in patients with HF.

Okita K, et al. Circulation 1998; 98: 1886-91

IMC

L (

mm

ol/

kg w

et w

eigh

t)

ppm

Control

HF

3 2 1 0 Control HF

*

EMCL

IMCL

IMCL

EMCL

Intramyocellular lipid (IMCL)

TCr

TCr

0

2

4

6

8

Hirabayashi K, et al. Int J Cardiol 2014;176:1110-2

Association between IMCL and exercise capacity

0

10

20

30

40

0 2 4 60

10

20

30

0 2 4 6

0

20

40

60

80

0 2 4 6

IMCL content

(mmol/kg wet weight)

IMCL content

(mmol/kg wet weight)

IMCL content

(mmol/kg wet weight)

Peak

VO

2 (

mL

/kg/m

in)

AT

(m

L/k

g/m

in)

PC

r lo

ss (

%)

r=-0.589, p<0.01 r=-0.602 , p<0.01 r=0.630, p<0.01

Control (n=12)

HF (n=18)

Hirabayashi K, et al. Int J Cardiol 2014;176:1110-2

Hülsmann M, et al. Eur J Heart Fail 2004; 6: 101-7

Survival rate is lower in low knee flexors strength group

(<68NmX100/kg) than in high group.

Muscle strength and survival rate

0

20

40

60

80

100

0 10 20 30 40 50 60

Su

rviv

al

rate

(%

) High strength (n=49)

Low strength (n=42)

Follow up (months)

Skeletal muscle mass and muscle strength/endurance capacity

Fulster S, et al. Eur Heart J. 2013;34:512-9

20

30

40

50

20

30

40

50

60

500

1000

1500

2000

0

3

6

9

12

15

Muscle atrophy

*

* * *

Muscle strength Endurance capacity

- +

Muscle atrophy

- +

Muscle atrophy

- +

Muscle atrophy

- +

Ha

nd

gri

p (

kg

)

Qu

ad

rice

ps

(kg

)

Ex

erci

se t

ime

(min

)

Pea

k V

O2 (

mL

/kg

)

Sarcopenia and HF

• Elderly people aged 60 to 70 years with sarcopenia are 5 to 13 %.

• HF patients (mean age of 66.9) with sarcopenia are 19.5%.

von Haehling S. et al. Int J Biochem Cell Biol. 2013; 45: 2257-65

Ca

rdia

c ev

ent

free

(%

)

Follow up (day)

0

20

40

60

80

100

0 200 400 600 800

ー Sarcopenia (-)

ー Sarcopenia (+)

Onoue Y, et al. Int J Cardiol. 2016; 215: 301-6

Fulster S, et al. Eur Heart J. 2013;34:512-9

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.

Impaired mitochondrial

function and decrease in

mitochondrial volume

Muscle atrophy and

decrease in muscle

strength

AMP

ATP

[Ca2+]

Transcription

Nucleus

β-oxidation

β-HAD

Mitochondrion TCA cycle NADH

FADH2

ATP

CO2

NAD+

FAD

ADP+Pi

Acetyl-CoA

AdipoR1

CaMKK

CaMK

PGC1α

AMPKα SIRT1

SIRT3

NAD+

NADH

ROS

NO

eNOS

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

AT1R

RAS

Nox

Signal regulating mitochondrial biogenesis

Kinugawa et al. Int Heart J 2015; 56:475-84

4E-BP p70S6K1

Translation

eIF4E S6

Protein synthesis Protein degradation

FoxO

mTORC2

p38 MAPK

TNFR ActRIIB IGF1R

ROS

PI3K

mTORC1

Smad2/3

GR

eIF2B

GSK3β mTOR

MuRF1 Atrogin 1

Akt

AT1R Nox

TNFα Myostatin RAS IGF1 Glucocorticoid

IKK

NFκB

IκB

Signal regulating protein synthesis and degradation

Kinugawa et al. Int Heart J 2015; 56:475-84

Mu

scle

cro

ss s

ecti

on

al a

rea

(μ

m2)

Ang II

100 μm

Vehicle

1 week 4 weeks

20

25

30

1 wk 4 wks

Bo

dy

wei

gh

t (g

)

*

0

□ Vehicle ■ Ang II

1 week 4 weeks

0

500

1000

1500

2000

2500

1 wk 4 wks

*

1 week 4 weeks

skel

eta

l m

usc

le w

eig

ht

(mg

)

300

320

340

360

380

400

420

1 wk 4 wks1 week 4 weeks

*

Ang II induces muscle atrophy in mice

Kadoguchi T, et al. Exp Physiol 2015; 100: 312-22

0

50

100

150

200

1 wk 4 wks

CS

act

ivit

y

(nm

ol/

min

/mg

pro

tein

)

* *

□ Vehicle ■ Ang II

Vehicle

1 wk 4 wks

Ang II

Type I

Type IIb

Type IIa

0

10

20

30

40

50

1 wk 4 wks

0

10

20

30

40

50

1 wk 4 wks

0

10

20

30

40

50

1 wk 4 wks

* *

Typ

e I

(%)

Typ

e II

a (

%)

Typ

e II

b (

%)

100 μm

0

100

200

300

400

500

1 wk 4 wks

Co

mp

lex

I

(nm

ol/

min

/mg

pro

tein

)

* *

Co

mp

lex

III

(nm

ol/

min

/mg

pro

tein

)

0

100

200

300

400

500

600

1 wk 4 wks

* *

1 week 4 weeks 1 week 4 weeks 1 week 4 weeks

1 week 4 weeks 1 week 4 weeks 1 week 4 weeks

Ang II induces mitochondrial dysfunction in

skeletal muscle and transition of fiber type

Kadoguchi T, et al. Exp Physiol 2015; 100: 312-22

0

5

10

15

20

1 wk 4 wks

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1 wk 4 wks

Vehicle

1 wk 4 wks

Ang II T

UN

EL

po

siti

ve

nu

clei

(%

)

Cleaved

caspase-3

GAPDH

1 wk 4 wks

Cle

av

ed c

asp

ase

-3/G

AP

DH

* *

* □ Vehicle ■ Ang II 100 μm

*

1 week 4 weeks 1 week 4 weeks

Ang II induces apoptotic cell death in skeletal muscle

Kadoguchi T, et al. Exp Physiol 2015; 100: 312-22

0

50

100

150

200

1 wk 4 wks

0

500

1000

1 wk 4 wks

NA

D(P

)H o

xid

ase

act

ivit

y

(RL

U/m

in/1

00

µg

pro

tein

)

*

*

□ Vehicle ■ Ang II

*

1 week 4 weeks 1 week 4 weeks

Lu

cig

enin

ch

emil

um

ines

cen

ce

(RL

U/m

in/m

g)

*

Ang II enhances ROS by activated NAD(P)H

oxidase in skeletal muscle

Kadoguchi T, et al. Exp Physiol 2015; 100: 312-22

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

Ang II induces all skeletal muscle abnormalities

clinically observed in HF

Ang II ROS Skeletal muscle abnormalities

Okita K, et al. Circ J 2013; 77: 293-300

Pedersen BK, et al. Nat Rev Endocrinol 2012; 8: 457-65

Skeletal muscle is a huge endocrine organ

Conclusion

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 not perform exercise.

We need to clarify the mechanism for skeletal muscle

abnormalities in HF and to develop new treatment targeting

them.