Age-environment interaction influencing skeletal muscle satellite cell function

描述（由申请人提供）：肌肉减少症是一种与年龄相关的骨骼肌质量和强度损失。最近的估计表明，多达45%的美国老年人患有肌肉减少症。肌肉减少症的严重临床结局包括身体虚弱的发作，导致失去独立生活，增加疗养院的使用，以及死亡率的逐渐增加。肌肉减少症的一个促成因素是老年骨骼肌再生、肥大和在一轮萎缩后再生长的能力减弱。在骨骼肌中，负责骨骼肌生长和修复的常驻干细胞被称为卫星细胞。最近的证据表明，与年龄相关的卫星细胞功能丧失是导致老年骨骼肌再生潜力丧失和萎缩和纤维化增加的主要因素。长期目标是更好地了解调节卫星细胞功能的机制，以促进治疗策略的发展。卫星细胞的功能在很大程度上取决于周围环境。然而，我们也知道，与从年轻肌肉中分离的卫星细胞相比，来自老年骨骼肌的卫星细胞对环境的反应不同。关键的潜在问题是卫星细胞/环境相互作用如何促进衰老中受损的骨骼肌再生/肥大/再生长？衰老与慢性低度全身性炎症相关，慢性低度全身性炎症是一种通过某些细胞因子（包括TNF-1、IL-1和IL-6）的循环水平增加约2至3倍来鉴定的病症。有趣的是，已知TNF-1和IL-12均引起IL-6表达，其具有促纤维化功能。重要的是，与年轻肌肉相比，老年骨骼肌中的卫星细胞表现出肌源性-纤维化谱系转变和受损的损伤再生反应。具体目标#1将确定负责观察到的IL-12诱导的IL-6表达的年龄依赖性差异的机制。具体而言，具体目标#1将确定IL-6表达的增加的转录调节、mRNA稳定性的贡献，以及内源性IL- 12诱导的TNF-1表达对从老化骨骼肌分离的卫星细胞中增加的IL-6表达的贡献。此外，将确定IL-12处理的卫星细胞中纤维化基因表达的年龄相关差异。这些发现将对确定衰老中卫星细胞功能减弱的潜在机制产生影响。具体目标#2将确定挫伤后增加IL-12治疗是否增加体内IL-6表达和骨骼肌纤维化。此外，具体目标#2将测试用抗IL-12治疗（重组IL-1受体拮抗剂）治疗是否可以减少损伤后的IL-6表达和骨骼肌纤维化。该提案的总体目标是确定增加的IL-12，TNF-1和IL-6是否在损伤后卫星细胞功能下降和骨骼肌纤维化增加中发挥作用。这些发现将对未来的干预措施产生影响，这些干预措施旨在增加我们老龄化和身体虚弱人群的骨骼肌质量和力量。

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.