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Exploring novel therapies for frailty and muscle disease

P. Gregorevic, Baker IDI Heart & Diabetes Institute, PO Box 6492, St Kilda Rd Central, VIC 8008, Australia.

Loss of skeletal muscle mass and strength is a common and significant contributor to impaired health and premature mortality. As the Transforming Growth Factor-beta (TGF-β) signalling network prominently regulates skeletal muscle development and post-natal growth, manipulation of cellular events that are governed by TGF-β signalling may provide a means to prevent or treat muscle-related disease. In mice, we have observed that local expression of follistatin (an inhibitor of the TGF-β family ligands, myostatin and activin A) can promote a 100% increase in muscle mass and >50% increase in maximum force producing capacity concomitant with increased protein synthesis and activation of the mammalian target of rapamycin (mTOR) pathway. However, the observed follistatin-mediated hypertrophic effects also occur independently of over-expression, or knock-out of myostatin a key repressor of muscle development that inhibits mTOR signaling. We have determined that follistatin-mediated muscle hypertrophy is also associated with, and is influenced by modulation of Smad-dependent signaling, which controls an extensive program of gene expression in skeletal muscle.

These data advance our understanding of the cellular mechanisms employed to promote follistatin-mediated skeletal muscle hypertrophy. As a prospective approach for combating frailty resulting from muscle wasting and dysfunction, we have examined the effects of follistatin expression in animal models of muscle-related disease and have observed differing responsiveness to acute follistatin expression. We propose that these distinct outcomes reflect the direct and indirect involvement of the TGF-β pathway in muscle wasting conditions of differing etiology. These data support further examination of the potential for developing TGF-β pathway-based therapeutic interventions for muscle-related disease.

All studies involving the use of animals were performed in accordance with federal guidelines on the appropriate conduct for care and use of animals in experimental research.
PG is supported by a project grant from the National Health & Medical Research Council, and the Pfizer Australia Senior Research Fellowship.