Age-related Changes in a Myogenic Niche

描述（由申请人提供）： 骨骼肌组织具有巨大的再生能力，在严重损伤和老化时会受到损害。最近针对老龄化人群中肌肉质量和肌肉功能损失的临床研究得出结论，包含脂肪是年龄相关性肌肉减少症的重要贡献者（Goodpasteretal.，2001; Pahorand Kritchevsky，1998; Sowers埃塔尔，2005年）。导致骨骼肌中脂肪积累增加的细胞的起源尚不清楚。然而，大量的轶事证据表明骨骼肌卫星细胞可能参与其中。这些细胞夹在肌纤维的基膜和质膜之间，负责骨骼肌组织的维持和修复，具有干细胞样性质（Hawke和Garry，2001; Schultz和McCormick，1994;西尔等人，2001;西尔和Rudnicki，2000; Wagers和Conboy，2005），并且能够在培养物中成骨和成脂分化（Wada等，2002年）。从老年啮齿动物培养的卫星细胞获得脂肪形成表型（Taylor-Jones et al.，2002年）。我们实验室最近发表和未发表的工作表明，syndecan-3 null和syndecan-4 null小鼠的未受伤肌肉含有过量的脂肪沉积。此外，来自这些小鼠的卫星细胞不能在具有多配体蛋白聚糖-4缺失细胞的培养物中分化，表现出脂肪形成的同时增强（Cornelison et al.，2004年）。多配体蛋白聚糖是环境信息和细胞粘附的关键介质，对于识别局部微环境是理想的（Tkachenko等人，2005年）。有趣的是，比较Syndecan-3和Syndecan-4空卫星细胞与野生型细胞的微阵列数据确定了焦点adesion/肌动蛋白细胞骨架信号转导转录本的主要变化以及调节脂肪形成的基因的诱导。我们提出，类似的机制是负责积累的脂肪沉积在骨骼肌从老年野生型小鼠，syndecan-4 null和syndecan-3 null小鼠，我们建议，卫星细胞需要一个环境的小生境，以保持肌原性的身份和承诺肌原性分化。这种生态位的改变或卫星细胞对生态位识别的丧失使它们能够致力于替代分化途径。为了验证这一假设，我们建议（i）表征体内肌肉再生过程中的脂肪沉积，（ii）确定体内脂肪积累的细胞群，（iii）评估所确定的因子在调节培养物中卫星细胞成脂转化中的作用。

DESCRIPTION (provided by applicant): Skeletal muscle tissue possesses a tremendous capacity for regeneration that is compromised upon severe injury and upon aging. Recent clinical studies addressing loss of muscle mass and muscle function in an ageing population conclude that inclusion of fat is a significant contributor to age-related sarcopenia (Goodpasteretal., 2001; Pahorand Kritchevsky, 1998; Sowers etal., 2005). The origins of cells that contribute to increased fat accumulation in skeletal muscle are not known. However, substantial anecdotal evidence exists to suggest that skeletal muscle satellite cells may be involved. These cells, sandwiched between the basal lamina and plasma membrane of myofibers are responsible for maintenance and repair of skeletal muscle tissue, possess stem cell-like properties (Hawke and Garry, 2001; Schultz and McCormick, 1994; Seale et al., 2001; Seale and Rudnicki, 2000; Wagers and Conboy, 2005) and are capable of osteogenic and adipogenic differentiation in culture (Wada et al., 2002). Satellite cells cultured from aged rodents acquire adipogenic phenotypes (Taylor-Jones et al., 2002). Recent published and unpublished work from our laboratory shows that uninjured muscle from syndecan-3 null and syndecan-4 null mice contain excess fat deposition. Moreover, satellite cells from these mice fail to differentiate in culture with syndecan-4 null cells exhibiting a concurrent enhancement of adipogenesis (Cornelison et al., 2004). The syndecans are critical mediators of environmental information and cell adhesion, ideal for recognizing local microenvironments (Tkachenko et al., 2005). Interestingly, microarray data comparing Syndecan-3 and Syndecan-4 null satellite cells with wt cells identifies major changes in focal adesion/actin cytoskeleton signaling transcripts as well as induction of genes that regulate adipogenesis. We propose that similar mechanisms are responsible for accumulation of fat deposits in skeletal muscle from aged wt mice, syndecan-4 null and syndecan-3 null mice where we propose that satellite cells require an environmental niche to maintain myogenic identity and commitment to myogenic differentiation. Alterations in this niche or loss of niche recognition by satellite cells allows them to commit to alternate differentiation pathways. To test this hypothesis, we propose to (i) characterize fat deposition during muscle regeneration in vivo, (ii) identify the cell populations contributing to fat accumulation in vivo, and (iii) assess the role of identified factors in regulating adipogenic conversion of satellite cells in culture.