Age-environment interaction influencing skeletal muscle satellite cell function

描述(由申请人提供)：骨质疏松症是一种与年龄相关的骨骼肌质量和力量的丧失。最近的估计显示，多达45%的美国老年人口患有骨质疏松症。骨质疏松症的严重临床后果包括身体虚弱导致丧失独立生活能力、疗养院使用率增加和死亡率逐渐增加。造成骨质疏松症的一个因素是衰老的骨骼肌再生、肥大和萎缩后再生的能力减弱。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衰老骨骼肌再生能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卫星细胞功能的调节机制，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的环境。然而，与分离自年轻肌肉的卫星细胞相比，来自老年骨骼肌的卫星细胞对环境的反应也是不同的。关键的潜在问题是，卫星细胞/环境的相互作用如何促进衰老过程中受损的骨骼肌再生/肥大/再生长？衰老与慢性低度全身炎症有关，这是一种通过循环中某些细胞因子水平增加~2-3倍来识别的疾病，包括肿瘤坏死因子-1、白介素1和白介素6。有趣的是，已知的肿瘤坏死因子-1和IL-12都能引起IL-6的表达，IL-6具有促纤维化作用。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向纤维性谱系的转变，损伤后再生反应受损。具体目标1将确定导致观察到的IL-12诱导的IL-6表达与年龄相关的差异的机制。具体地说，特定的目标#1将确定IL-6表达的转录调节增加的贡献，mRNA的稳定性，以及内源性IL-12诱导的肿瘤坏死因子-1的表达对老年骨骼肌分离的卫星细胞IL-6表达增加的贡献。此外，IL-12处理的卫星细胞中纤维化基因表达的年龄差异将被确定。这一发现将对确定衰老过程中卫星细胞功能减弱的潜在机制具有重要意义。具体目标#2将确定挫伤后增加IL-12治疗是否会增加体内IL-6的表达和骨骼肌纤维化。此外，特殊目标#2将测试抗IL-12治疗(重组IL-1受体拮抗剂)是否可以减少IL-6的表达和损伤后的骨骼肌纤维化。该提案的总体目标是确定IL-12、TNF-1和IL-6的增加是否在损伤后卫星细胞功能下降和骨骼肌纤维化增加中起作用。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。 公共卫生相关性：众所周知，衰老与免疫功能改变有关。在骨骼肌方面，这些发现将有助于开发针对改变的免疫反应的治疗方法，以改善卫星细胞在衰老过程中的功能，从而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. 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.