Adipokine Regulation Of Myostatin Signaling In Aged Skeletal Muscle

Abstract

Skeletal muscle atrophies with age, a phenomenon referred to as the sarcopenia of aging. The secreted factor myostatin (GDF-8) is known to suppress myofiber hypertrophy and induce muscle atrophy, and elevated myostatin expression has been implicated in muscle loss with aging. Myostatin expression may be regulated in part by the fat-derived hormone leptin. Mice lacking leptin have reduced muscle mass and elevated myostatin expression, which can be reversed with recombinant leptin therapy. PURPOSE: To determine the effects of leptin treatment on muscle mass and myostatin signaling in aged skeletal muscle. METHODS: C57BL/6 mice 12 and 24 months of age received daily subcutaneous injections of either vehicle (saline) or recombinant leptin (10 μg/day) for 10 days. Mice were euthanized after the 10 day treatment period and body weight and quadriceps mass recorded. The extensor digitorum longus (EDL) was dissected free, embedded in OCT medium, and snap frozen. Muscle fiber cross-sectional areas were measured from cryostat sections of the EDL, and real-time PCR used to quantify expression of myostatin and its receptor (ActRIIB) from the tibialis anterior. RESULTS: Leptin treatment did not significantly alter body weight in mice of either age group, but quadriceps muscle weights were significantly lower (P<.001) in the aged mice. Leptin treatment significantly increased quadriceps muscle mass both absolutely (P<.05) and relative to body mass (P<.01) in the aged mice but not in the younger mice. Muscle fiber cross-sectional areas of the extensor digitorum longus muscle (EDL) were slightly lower in aged mice, and leptin treatment significantly (P<.05) increased EDL fiber area in the aged mice but not the young mice. Leptin treatment was found to decrease myostatin expression by ∼40% and ActRIIB expression by ∼50% in the tibialis anterior of aged mice compared to that of saline-treated aged mice. CONCLUSIONS: Results from our study support the hypothesis that the adipokine leptin is a key factor linking nutrient intake with normal muscle function, and reveal that leptin can alter myostatin signaling in aged muscle. Recombinant leptin treatment may therefore have potential as a novel therapeutic approach for the prevention of sarcopenia. Supported by US Army Medical Research Acquisition Activity Award PR093619