Myostatin represses physiological hypertrophy of the heart and excitation-contraction coupling.
Although myostatin negatively regulates skeletal muscle growth, its function in heart is virtually unknown. Herein we demonstrate that it inhibits basal and IGF-stimulated proliferation and differentiation and also modulates cardiac excitation-contraction (EC) coupling. Loss of myostatin induced eccentric hypertrophy and enhanced cardiac responsiveness to beta-adrenergic stimulation in vivo. This was due to myostatin null ventricular myocytes having larger [Ca(2+)](i) transients and contractions and responding more strongly to beta-adrenergic stimulation than wild-type cells. Enhanced cardiac output and beta-adrenergic responsiveness of myostatin null mice was therefore due to increased SR Ca(2+) release during EC coupling and to physiological hypertrophy, but not to enhanced myofilament function as determined by simultaneous measurement of force and ATPase activity. Our studies support the novel concept that myostatin is a repressor of physiological cardiac muscle growth and function. Thus, the controlled inhibition of myostatin action could potentially help repair damaged cardiac muscle by inducing physiological hypertrophy.
Rodgers
Buel D
BD
Department of Animal Sciences and School of Molecular Biosciences, Washington State University, Pullman, WA 99164, USA. danrodgers@wsu.edu
Interlichia
Jillian P
JP
Garikipati
Dilip K
DK
Mamidi
Ranganath
R
Chandra
Murali
M
Nelson
O Lynne
OL
Murry
Charles E
CE
Santana
Luis F
LF
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly / Q000503:physiopathology; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D006321:Heart / Q000187:drug effects / Q000502:physiology; D006331:Heart Diseases / Q000188:drug therapy / Q000503:physiopathology; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D055435:Myostatin / Q000378:metabolism* / Q000627:therapeutic use; D051381:Rats; D012038:Regeneration
D000318:Adrenergic beta-Agonists; D055435:Myostatin; D007545:Isoproterenol; D002118:Calcium