The
transforming growth factor-β (TGF-β) signaling network is a critical regulator of skeletal muscle mass and function and, thus, is an attractive therapeutic target for combating muscle disease, but the underlying mechanisms of action remain undetermined. We report that
follistatin-based interventions (which modulate TGF-β network activity) can promote muscle
hypertrophy that ameliorates aging-associated muscle wasting. However, the muscles of old sarcopenic mice demonstrate reduced response to
follistatin compared with healthy young-adult musculature. Quantitative proteomic and transcriptomic analyses of young-adult muscles identified a transcription/translation signature elicited by
follistatin exposure, which included repression of ankyrin repeat and SOCS box
protein 2 (Asb2). Increasing expression of ASB2 reduced muscle mass, thereby demonstrating that Asb2 is a TGF-β network-responsive negative regulator of muscle mass. In contrast to young-adult muscles, sarcopenic muscles do not exhibit reduced ASB2 abundance with
follistatin exposure. Moreover, preventing repression of ASB2 in young-adult muscles diminished
follistatin-induced muscle
hypertrophy. These findings provide insight into the program of transcription and translation events governing
follistatin-mediated adaptation of skeletal muscle attributes and identify Asb2 as a regulator of muscle mass implicated in the potential mechanistic dysfunction between
follistatin-mediated muscle growth in young and old muscles.