Abnormalities of Calcium Handling Proteins in Skeletal Muscle Mirror Those of the Heart in Humans With Heart Failure: A Shared Mechanism?

doi:10.1016/j.cardfail.2012.07.005

Journal of Cardiac Failure

Volume 18, Issue 9, September 2012, Pages 724-733

https://doi.org/10.1016/j.cardfail.2012.07.005 Get rights and content

Abstract

Background

In the failing human heart, abnormalities of Ca²⁺ cycling have been described, but there is scant knowledge about Ca²⁺ handling in the skeletal muscle of humans with heart failure (HF). We tested the hypothesis that in humans with HF, Ca²⁺ cycling proteins in skeletal muscle are abnormal.

Methods and Results

Ten advanced HF patients (50.4 ± 3.7 years), and 9 age-matched controls underwent vastus lateralis biopsy. Western blot analysis showed that sarco(endo)plasmic reticulum Ca²⁺-ATPase (SERCA)2a, which is responsible for Ca²⁺ sequestration into the sarcoplasmic reticulum(SR), was lower in HF versus controls (4.8 ± 0.5 vs 7.5 ± 0.8 AU, P = .01). Although phospholamban (PLN), which inhibits SERCA2a, was not different in HF versus controls, phosphorylation (SER16 site) of PLN, which relieves this inhibition, was reduced (0.8 ± 0.1 vs 3.9 ± 0.9 AU, P = .004). Dihydropyridine receptors were reduced in HF, (2.1 ± 0.4 vs 3.6 ± 0.5 AU, P = .04). We tested the hypothesis that these abnormalities of Ca²⁺ handling protein content and regulation were due to increased oxidative stress, but oxygen radical scavenger proteins were not elevated in the skeletal muscle of HF patients.

Conclusion

In chronic HF, marked abnormalities of Ca²⁺ handling proteins are present in skeletal muscle, which mirror those in failing heart tissue. This suggests a common mechanism, such as chronic augmentation of sympathetic activity and autophosphorylation of Ca²⁺-calmodulin-dependent-protein kinase II.

Section snippets

Study Population

Advanced HF patients, New York Heart Association Class II-III who met the following criteria were recruited from the Ahmanson-UCLA Cardiomyopathy Center: 1) age 21 to 65 years, 2) left ventricular ejection fraction ≤35%, 3) HF duration ≥ 6 months, 4) no active ischemia or ischemic event within 3 months, 5) not involved in a formal exercise training program, 6) on stable HF medications for ≥ 3 months, and 7) not taking warfarin. Age- and sex-matched healthy, nonsmoking controls, without chronic

Study Population Characteristics

Ten advanced HF patients and 9 healthy controls participated in these studies. Study population characteristics are displayed in Table 2. Patients and controls did not differ in age, sex, or body mass index. Of note, patients had chronic HF (mean duration 9.5 ± 1.9 years) and had severe exercise limitation as estimated by peak oxygen consumption of 11.6 ± 1.0 mL·kg·min.

Morphometric Analysis

Individual mean type 1 fiber percentage is shown in Figure 1a. Mean type 1 fiber type percentage in our HF patients was 30.6 ±

Discussion

The major, novel findings in this study of chronic, advanced HF patients on optimal medical therapy with severely limited exercise tolerance are: 1) SERCA2a and DHPR protein content in skeletal muscle are significantly decreased in HF patients compared with healthy controls, 2) p-PLN content and the p-PLN/PLN ratio in skeletal muscle are markedly decreased in HF patients compared with healthy controls, and 3) the lack of increase, and in fact significant decrease, in HSP and ROS scavenger

Acknowledgments

The authors wish to thank Dr. James N. Weiss for his insights and thoughtful comments on this work.

Disclosures

None.

References (49)

C.S. Maskin et al.
Failure of dobutamine to increase exercise capacity despite hemodynamic improvement in severe chronic heart failure
Am J Cardiol
(1983)
D. Harrington et al.
Skeletal muscle function and its relation to exercise tolerance in chronic HF
J Am Coll Cardiol
(1997)
D.M. Bers
Ca2+-calmodulin-dependent protein kinase II regulation of cardiac excitation-transcription coupling
Heart Rhythm
(2011)
D. Gupta et al.
Improved exercise capacity and reduced systemic inflammation after adenoviral-mediated SERCA-2a gene transfer
J Surg Res
(2008)
N.W. Seidler et al.
Cyclopiazonic acid is a specific inhibitor of the Ca²⁺-ATPase of sarcoplasmic reticulum
J Biol Chem
(1989)
H.R. Gosker et al.
Skeletal muscle dysfunction in chronic obstructive pulmonary disease and chronic heart failure: underlying mechanisms and therapy perspectives
Am J Clin Nutr
(2000)
K. O'Connell et al.
Reduced expression of sarcalumenin and related Ca²⁺-regulatory proteins in aged rat skeletal muscle
Exp Gerontol
(2008)
P. Nicolaou et al.
Role of protein phosphatase-1 inhibitor-1 in cardiac physiology and pathophysiology
J Molec Cell Cardiol
(2009)
M.E. Anderson et al.
CaMKII in myocardial hypertrophy and heart failure
J Mol Cell Cardiol
(2011)
P.A. Ruell et al.
Measurement of sarcoplasmic reticulum function in mammalian skeletal muscle: technical aspects
Anal Biochem
(1995)

J.A. Franciosa et al.

Lack of correlation between exercise capacity and indices of resting left ventricular performance in heart failure

Am J Cardiol

(1991)

M. Higginbotham et al.

Determinants of variable exercise performance among patients with severe left ventricular dysfunction

Am J Cardiol

(1983)

H.R. Middlekauff

Making the case for skeletal myopathy as the major limitation of exercise capacity in heart failure

Circ Heart Fail

(2010)

P.K. Lunde et al.

Skeletal muscle disorders in heart failure

Acta Physiol Scand

(2001)

G. Hasenfuss

Alterations of calcium-regulatory proteins in heart failure

Cardiovasc Res

(1998)

D.M. Bers

Excitation-Contraction Coupling and Cardiac Contractile Force

(2001)

S. Reiken et al.

PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure

J Cell Biol

(2003)

N.P. Rolim et al.

Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure

Physiol Genom

(2007)

K.R. Shah et al.

Changes in skeletal muscle SR Ca²⁺ pump in congestive heart failure due to myocardial infarction are prevented by angiotensin II blockade

Can J Physiol Pharmacol

(2004)

C.R. Bueno et al.

Aerobic exercise training improves skeletal muscle function and Ca2+ handling-related proteins expression in sympathetic hyperactivity-induced heart failure

J Appl Physiol

(2010)

P.K. Lunde et al.

Contraction and intracellular Ca²⁺handling in isolated skeletal muscle of rats with congestive heart failure

Circ Res

(2001)

C.L. Perreault et al.

Alterations in contractility and intracellular Ca2+ transients in isolated bundles of skeletal muscle fibers from rats with chronic heart failure

Circ Res

(1993)

M. Munkvik et al.

Training effects on skeletal muscle calcium handling in human chronic heart failure

Med Sci Sports Exerc

(2010)

R.C. Gupta et al.

Cardiac SR-coupled PP1 activity and expression are increased and inhibitor 1 protein expression is decreased in failing hearts

Am J Physiol Heart Circ Physiol

(2003)

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: Supported by NIH-RO1 HL084525 (H.R.M.), the University of California, Los Angeles, General Clinical Research Center NIH-MO1-RR00865, and the Natural Sciences and Engineering Research Council of Canada (NSERC) 311922 (A.R.T.). C. Vigna was supported by a PGS-D award from NSERC.

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Clinical InvestigationAbnormalities of Calcium Handling Proteins in Skeletal Muscle Mirror Those of the Heart in Humans With Heart Failure: A Shared Mechanism?

Abstract

Background

Methods and Results

Conclusion

Section snippets

Study Population

Study Population Characteristics

Morphometric Analysis

Discussion

Acknowledgments

Disclosures

Am J Cardiol

J Am Coll Cardiol

Heart Rhythm

J Surg Res

J Biol Chem

Am J Clin Nutr

Exp Gerontol

J Molec Cell Cardiol

J Mol Cell Cardiol

Anal Biochem

Lack of correlation between exercise capacity and indices of resting left ventricular performance in heart failure

Am J Cardiol

Determinants of variable exercise performance among patients with severe left ventricular dysfunction

Am J Cardiol

Making the case for skeletal myopathy as the major limitation of exercise capacity in heart failure

Circ Heart Fail

Skeletal muscle disorders in heart failure

Acta Physiol Scand

Alterations of calcium-regulatory proteins in heart failure

Cardiovasc Res

Excitation-Contraction Coupling and Cardiac Contractile Force

PKA phosphorylation activates the calcium release channel (ryanodine receptor) in skeletal muscle: defective regulation in heart failure

J Cell Biol

Exercise training improves the net balance of cardiac Ca2+ handling protein expression in heart failure

Physiol Genom

Changes in skeletal muscle SR Ca2+ pump in congestive heart failure due to myocardial infarction are prevented by angiotensin II blockade

Can J Physiol Pharmacol

Aerobic exercise training improves skeletal muscle function and Ca2+ handling-related proteins expression in sympathetic hyperactivity-induced heart failure

J Appl Physiol

Contraction and intracellular Ca2+handling in isolated skeletal muscle of rats with congestive heart failure

Circ Res

Alterations in contractility and intracellular Ca2+ transients in isolated bundles of skeletal muscle fibers from rats with chronic heart failure

Circ Res

Training effects on skeletal muscle calcium handling in human chronic heart failure

Med Sci Sports Exerc

Cardiac SR-coupled PP1 activity and expression are increased and inhibitor 1 protein expression is decreased in failing hearts

Am J Physiol Heart Circ Physiol

Clinical Investigation
Abnormalities of Calcium Handling Proteins in Skeletal Muscle Mirror Those of the Heart in Humans With Heart Failure: A Shared Mechanism?

Changes in skeletal muscle SR Ca²⁺ pump in congestive heart failure due to myocardial infarction are prevented by angiotensin II blockade

Contraction and intracellular Ca²⁺handling in isolated skeletal muscle of rats with congestive heart failure