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Myostatin Is a Skeletal Muscle Target of Growth Hormone Anabolic Action

Department of Medicine (W.L., S.E.), Mount Sinai Hospital and University of Toronto; Faculty of Physical Education and Health (S.G.T.), University of Toronto; Department of Laboratory Medicine and Pathobiology, University Health Network and University of Toronto, Freeman Centre for Endocrine Oncology, and Ontario Cancer Institute (S.L.A.), Toronto, Ontario, Canada M5G 2M9; and Division of Endocrinology, Metabolism and Molecular Medicine (N.G.-C., S.B.), Charles R. Drew University of Medicine and Science, Los Angeles, California 90059

Address all correspondence and requests for reprints to: Dr. S. Ezzat, University of Toronto–Mt. Sinai Hospital, 600 University Avenue, #437, Toronto, Ontario, Canada M5G-1X5. E-mail: sezzat{at}mtsinai.on.ca.

Myostatin is a cytokine that has recently been shown to selectively and potently inhibit myogenesis. To investigate the mechanisms of anabolic actions of GH on skeletal muscle growth, we examined the in vitro and in vivo effects of GH on myostatin regulation. Twelve GH-deficient hypopituitary adult subjects were treated with recombinant GH (5 µg/kg·d) in a double-blind, placebo-controlled fashion. Body composition and physical function were assessed and skeletal muscle biopsies from the vastus lateralis performed at 6-monthly intervals during 18 months of treatment. Myostatin mRNA expression was significantly inhibited to 31 ± 9% (P < 0.001) of control by GH but not by placebo administration (79 ± 11%) as determined by quantitative real-time PCR normalized for the housekeeping glyceraldehyde-3-phosphate dehydrogenase gene. The inhibitory effect of GH on myostatin was sustained after 12 and 18 months of GH treatment. These effects were associated with increases in lean body mass and translated into enhanced aerobic performance as determined by maximal oxygen uptake and ventilation threshold. Parallel in vitro studies of skeletal muscle cells demonstrated significant reduction of myostatin expression by myotubes in response to GH, compared with vehicle treatment. Conversely, GH receptor antagonism resulted in up-regulation of myostatin in myoblasts. Given the potent catabolic actions of myostatin, our data suggest that myostatin represents a potential key target for GH-induced anabolism.

Abbreviations: GAPDH, Glyceraldehyde-3-phosphate dehydrogenase; GHD, GH deficiency; GHR, GH receptor; SPW, self-paced walking; VeT, ventilation threshold; VO₂max, maximum oxygen uptake.

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