Age-environment interaction influencing skeletal muscle satellite cell function

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DESCRIPTION (provided by applicant): Sarcopenia is an age-associated loss of skeletal muscle mass and strength. Recent estimates suggest that as much as 45% of the older U.S. population suffers from sarcopenia. Grave clinical outcomes of sarcopenia include the onset of physical frailty leading to the loss of independent living, increased nursing home utilization, and progressive increase in mortality. One contributing factor to sarcopenia is the diminished capacity for aged skeletal muscle to regenerate, hypertrophy, and regrow after a bout of atrophy. In skeletal muscle, the resident stem cells responsible for skeletal muscle growth and repair are termed satellite cells. Recent evidence suggests that an age-associated loss of satellite cell functionality is the primary factor responsible for the loss of regenerative potential and increased atrophy and fibrosis of aged skeletal muscle. The long-term objective is to gain a better understanding of mechanisms regulating satellite cell function in order to facilitate the development of therapeutic strategies. Satellite cell function is largely dictated by the surrounding environment. However, it is also known that satellite cells from aged skeletal muscle respond to the environment differently, compared to satellite cells isolated from young muscle. The key underlying question is how do the satellite cell/environment interactions contribute to impaired skeletal muscle regeneration/hypertrophy/regrowth in aging? Aging is associated with chronic low-grade systemic inflammation, which is a condition that is identified by a ~2- to 3-fold increase in circulating levels of certain cytokines including TNF-1, IL-1, and IL-6. Interestingly, both TNF-1 and IL-12 are known to cause IL-6 expression, which has pro-fibrotic function. Importantly, satellite cells in aged skeletal muscle exhibit a myogenic-fibrogenic lineage transition and impaired regenerative response to injury, compared to young muscle. Specific aim #1 will determine the mechanisms responsible for the observed age-dependent differences in IL-12-induced IL-6 expression. Specifically, Specific Aim #1 will determine the contribution of increased transcriptional regulation of IL-6 expression, mRNA stability, and the contribution of endogenous IL- 12-induced TNF-1 expression to increased IL-6 expression in satellite cells isolated from aged skeletal muscle. Moreover, age-associated differences in fibrotic gene expression in IL-12 treated satellite cells will be determined. The findings will have implications for identifying underlying mechanisms responsible for diminished satellite cell function in aging. Specific Aim #2 will determine whether increased IL-12 treatment after contusion injury increases IL-6 expression and skeletal muscle fibrosis in vivo. Moreover, Specific Aim #2 will test whether treatment with an anti-IL-12 treatment (recombinant IL-1-receptor antagonist) can decrease IL-6 expression and skeletal muscle fibrosis after injury. The overall goal of the proposal is to determine whether increased IL-12, TNF-1, and IL-6 play a role in decreased satellite cell function and increased skeletal muscle fibrosis after injury. These findings will have implications for future interventions aimed at increasing skeletal muscle mass and strength in our aging and physically frail populations. PUBLIC HEALTH RELEVANCE: It is well established that aging is associated with altered immune function. In terms of skeletal muscle, these findings will facilitate the development of treatments designed to target the altered immune response in order to improve satellite cell function in aging, and therefore, increase skeletal muscle mass and strength in our aging and physically frail populations.