Promoting skeletal muscle growth is extremely important for medical conditions in which muscle wasting contributes to low quality of life, high health care costs, and institutionalization (i.e. aging, cachexia, congestive heart failure, etc.). It is well known that skeletal muscle hypertrophies in response to increased loading; however the mechanisms underlying this phenomenon remain poorly understood. In this respect, there is accumulating evidence that hormonal signaling and mechanical signaling (via focal adhesion complex proteins) may act synergistically and share common pathway intermediates such as focal adhesion kinase (FAK), serum response factor and other upstream/downstream elements. To examine this possibility, the current proposal consists of a strategy to tease out the individual and combined effects of angiotensin II signaling, insulin-like growth factor-I (IGF-1) signaling and integrin (mechanical) signaling in skeletal muscle hypertrophy. In the first specific aim, the PI proposes to confirm and extend upon two pilot experiments in which, using an overload model (via synergistic gastrocnemius ablation), compensatory hypertrophy of the rat soleus muscles is almost completely inhibited by the use of an ACE inhibitor. Although angiotensin II is a known stimulus to cardiac and smooth muscle growth, these findings in skeletal muscle are novel. The second specific aim consists of multiple experiments designed to a) in living rats, test the effect of angiotensin II alone, IGF-1 alone, and mechanical loading alone (rat resistance exercise model) on the acute (1 hr post stimulus) response of multiple downstream signaling elements common to these 3 stimuli in skeletal muscle; b) in living rats, test the effect of skeletal muscle loading on these downstream elements while either blocking endogenous angiotensin II input (receptor blockade or ACE inhibition), blocking endogenous IGF-1 input (receptor blockade), or blocking mechanical signaling (disrupting the integrin/extracellular matrix interface with RGD peptide); and, c) in cultured rat skeletal myotubes, test the effect of exogenous angiotensin II alone, exogenous IGF-1 alone, and stretch alone on these downstream elements. Finally, the third specific aim utilizes microarray technology to examine the overlap between these growth factor and mechanical stimuli at the level of mRNA expression in skeletal muscle of living rats. Elucidation of the mechanisms signaling skeletal muscle growth may lead to drugs, gene therapy, or other countermeasures against skeletal muscle wasting in individuals for whom exercise is perhaps impossible.
Showing the most recent 10 out of 60 publications
