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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR019393-28
Application #
6632593
Study Section
Respiratory and Applied Physiology Study Section (RAP)
Program Officer
Nuckolls, Glen H
Project Start
1979-08-01
Project End
2004-04-30
Budget Start
2003-05-01
Budget End
2004-04-30
Support Year
28
Fiscal Year
2003
Total Cost
$204,450
Indirect Cost
Name
University of Missouri-Columbia
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
153890272
City
Columbia
State
MO
Country
United States
Zip Code
65211
Booth, Frank W; Roberts, Christian K; Laye, Matthew J (2012) Lack of exercise is a major cause of chronic diseases. Compr Physiol 2:1143-211
Spangenburg, Espen E; Booth, Frank W (2006) Leukemia inhibitory factor restores the hypertrophic response to increased loading in the LIF(-/-) mouse. Cytokine 34:125-30
Machida, S; Booth, F W (2005) Changes in signalling molecule levels in 10-day hindlimb immobilized rat muscles. Acta Physiol Scand 183:171-9
Lees, Simon J; Booth, Frank W (2005) Physical inactivity is a disease. World Rev Nutr Diet 95:73-9
Booth, Frank W; Shanely, R Andrew (2004) The biochemical basis of the health effects of exercise: an integrative view. Proc Nutr Soc 63:199-203
Lees, Simon J; Booth, Frank W (2004) Sedentary death syndrome. Can J Appl Physiol 29:447-60; discussion 444-6
Rennie, Michael J; Wackerhage, Henning; Spangenburg, Espen E et al. (2004) Control of the size of the human muscle mass. Annu Rev Physiol 66:799-828
Machida, Shuichi; Booth, Frank W (2004) Regrowth of skeletal muscle atrophied from inactivity. Med Sci Sports Exerc 36:52-9
Spangenburg, Espen E; Bowles, Douglas K; Booth, Frank W (2004) Insulin-like growth factor-induced transcriptional activity of the skeletal alpha-actin gene is regulated by signaling mechanisms linked to voltage-gated calcium channels during myoblast differentiation. Endocrinology 145:2054-63
Chakravarthy, Manu V; Booth, Frank W (2004) Eating, exercise, and ""thrifty"" genotypes: connecting the dots toward an evolutionary understanding of modern chronic diseases. J Appl Physiol 96:3-10

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