Mechanisms of reduced regenerative potential in aging skeletal muscle

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DESCRIPTION (provided by applicant): As we age, the regenerative capacity of skeletal muscle declines, prolonging or preventing complete recovery and rehabilitation from muscle injury. In fact older adults often never recover muscle mass and strength following an injury; leading to fatigue, activity limitations, and ultimately a loss of independence. Background: Effective recovery of injured skeletal muscle is driven by activation of resident satellite cells. Concurrently, the inflammatory response clears cellular debris and promotes satellite cell differentiation. However, the inflammatory process can also delay recovery by damaging cellular components via oxidative stress. Satellite cells retain their regenerative potential throughout lif, if exposed to the proper environment. Therefore, dietary supplements designed to augment satellite cell activity and minimize oxidative stress have the potential to improve skeletal muscle rehabilitation following acute injury. Hypotheses and Approach: L-arginine can act as an antioxidant, as well as a stimulator of satellite cell activation in cell culture. Therefore, we propose a novel application of dietary L-arginine therapy to simultaneously augment satellite cell activity and inhibit inflammatory stress in vivo. This project will translate our preliminary cell culture data into an in vivo animal model and explore the mechanisms underlying the functional effects of L- arginine in adult skeletal muscle. We hypothesize that L-arginine supplementation following acute myotoxin injury will augment recovery of muscle mass by inhibiting activation of the inflammatory mediator, NF-kB, and enhancing activation of resident satellite cells. Further, that these effects will be dependent upon nitric oxide production. Significance: Physical rehabilitation following muscular injury is a major health care expense. More importantly, the loss of muscle mass with aging coupled with the failure to fully recover muscle following injury leads to physical frailty and increased risk of metabolic disease. Therefore, this project seeks to improve our mechanistic understanding of muscle regeneration and translate basic science data into effective dietary supplement strategies to augment muscle injury recovery. and contractile function in aging mice PUBLIC HEALTH RELEVANCE: Physical rehabilitation following muscular injury is a major health care expense, and the failure to fully recover muscle mass and strength after traumatic or contraction-induced injury leads to development of fatigability and activity limitations in older people, ultimately resulting in the loss of independence. Cell culture experiments suggest that L-arginine supplementation may offer a safe and effective method of stimulating muscle regeneration. Therefore, this project will explore the mechanisms behind L-arginine-induced regeneration in aging mouse skeletal muscle, and concurrently develop effective strategies for L-arginine supplementation in young and aging animals.