Cellular and Molecular Mechanisms of Chronic Inflammation in Aging of Skeletal Muscle

Abstract

Aging of skeletal muscle is typically accompanied by declining regenerative potential, due in part to alternations in the resident muscle stem cell population, known as satellite cells. Previous data suggest that highly regenerative satellite cells in young mice are damaged by aging and chronic inflammation, driven in part by the transcription factor NF-κB. Interestingly, myogenic function of aged satellite cells can be restored by exposure to blood-borne factors from young mice, in association with decreased expression of many of pro-inflammatory genes. These observations led me to hypothesize that strategies counteracting the chronic inflammatory state in muscle might improve regenerative function in old age through enhancement of satellite cell function. To test this hypothesis, this study aims to define the molecular factors that promote chronic muscle inflammation with aging, evaluate their impact on satellite cell functions, and determine whether inhibition of the inflammatory process indeed reverses age-related muscle dysfunction. Utilization of well-established mouse models reveals that NF-κB activity has a detrimental effect on satellite cell function via non-cell-autonomous mechanisms, and that inhibition of NF-κB activity and its downstream target phospholipase A2 in skeletal muscle fibers preserves muscle regenerative potential in aged animals. In addition, this study reports the restrictive role of IL-6, a pro-inflammatory cytokine widely recognized as a biomarker of chronic inflammation, on the myogenic function of satellite cells. Finally, this study shows that systemic inhibition of inflammation using the NF-κB antagonist sodium salicylate decreases inflammatory gene expression, including IL-6, in aged muscle and improves muscle regeneration after injury. Thus, chronic inflammation in muscle, in association with elevated NF-κB activity and its downstream pro-inflammatory factors, impairs muscle regeneration by extrinsically limiting the myogenic function of satellite cells in aged animals. Importantly, such impairment was shown to be reversible by reducing the inflammatory tone both at tissue and systemic level. By discovering the molecular mediators NF-κB signaling in muscle, this study provides potential therapeutic avenues for elderly patients with declining muscle mass and function.