Mechanisms of reduced regenerative potential in aging skeletal muscle

描述（由申请人提供）：随着年龄的增长，骨骼肌的再生能力下降，延长或阻止肌肉损伤的完全恢复和康复。事实上，老年人在受伤后往往无法恢复肌肉质量和力量；导致疲劳、活动受限，最终丧失独立性。背景：损伤骨骼肌的有效恢复是由常驻卫星细胞的激活所驱动的。同时，炎症反应清除细胞碎片并促进卫星细胞分化。然而，炎症过程也可以通过氧化应激破坏细胞成分来延缓恢复。如果暴露在适当的环境中，卫星细胞在整个生命周期中保持其再生潜力。因此，旨在增强卫星细胞活性和减少氧化应激的膳食补充剂具有改善骨骼肌的潜力

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