Genetic deletion of myostatin from the heart prevents skeletal muscle atrophy in heart failure.
BACKGROUND
Cardiac cachexia is characterized by an exaggerated loss of skeletal muscle, weakness, and exercise intolerance, although the cause of these effects remains unknown. Here, we hypothesized that the heart functions as an endocrine organ in promoting systemic cachexia by secreting peptide factors such as myostatin. Myostatin is a cytokine of the transforming growth factor-beta superfamily that is known to control muscle wasting.


RESULTS
We used a Cre/loxP system to ablate myostatin (Mstn gene) expression in a cell type-specific manner. As expected, elimination of Mstn selectively in skeletal muscle with a myosin light chain 1f (MLC1f)-cre allele induced robust hypertrophy in all skeletal muscle. However, heart-specific deletion of Mstn with an Nkx2.5-cre allele did not alter baseline heart size or secondarily affect skeletal muscle size, but the characteristic wasting and atrophy of skeletal muscle that typify heart failure were not observed in these heart-specific null mice, indicating that myocardial myostatin expression controls muscle atrophy in heart failure. Indeed, myostatin levels in the plasma were significantly increased in wild-type mice subjected to pressure overload-induced cardiac hypertrophy but not in Mstn heart-specific deleted mice. Moreover, cardiac-specific overexpression of myostatin, which increased circulating levels of myostatin by 3- to 4-fold, caused a reduction in weight of the quadriceps, gastrocnemius, soleus, and even the heart itself. Finally, to investigate myostatin as a potential therapeutic target for the treatment of muscle wasting in heart failure, we infused a myostatin blocking antibody (JA-16), which promoted greater maintenance of muscle mass in heart failure.


CONCLUSIONS
Myostatin released from cardiomyocytes induces skeletal muscle wasting in heart failure. Targeted inhibition of myostatin in cardiac cachexia might be a therapeutic option in the future.
Heineke
Joerg
J
Department of Pediatrics, University of Cincinnati, Cincinnati Children's Hospital Medical Center, Cincinnati, USA.
Auger-Messier
Mannix
M
Xu
Jian
J
Sargent
Michelle
M
York
Allen
A
Welle
Stephen
S
Molkentin
Jeffery D
JD
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D015153:Blotting, Western; D002100:Cachexia / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D015870:Gene Expression / Q000502:physiology; D055879:Gene Knock-In Techniques; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D032383:Myocytes, Cardiac / Q000378:metabolism; D055435:Myostatin / Q000235:genetics* / Q000276:immunology / Q000378:metabolism; D009928:Organ Specificity; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000906:Antibodies; C525912:Mstn protein, mouse; D055435:Myostatin