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受到损害。最近针对老龄化人群肌肉质量和肌肉功能损失的临床研究得出结论，脂肪是年龄相关性肌肉减少症的重要因素。, 2001;Pahorand Kritchevsky, 1998；苗圃等等。, 2005)。导致骨骼肌中脂肪堆积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底层和质膜之间，负责骨骼肌组织的维持和修复，具有干细胞样特性（Hawke和Garry, 2001； Schultz和McCormick, 1994； Seale等人，2001；Seale和Rudnicki, 2000； Wagers和Conboy， 2005），并且能够在培养中分化成骨和成脂（Wada等人，2002）。从老年啮齿动物培养的卫星细胞获得脂肪表型（Taylor-Jones et al., 2002）。我们实验室最近发表和未发表的研究表明，syndecan-3和syndecan-4缺失小鼠的未损伤肌肉含有多余的脂肪沉积。此外，来自这些小鼠的卫星细胞在与syndecan-4缺失细胞的培养中不能分化，同时表现出脂肪生成的增强（Cornelison et al., 2004）。syndecans是环境信息和细胞粘附的关键介质，是识别局部微环境的理想介质（Tkachenko et al., 2005）。有趣的是，将Syndecan-3和Syndecan-4零卫星细胞与wt细胞进行比较的微阵列数据发现，局灶性附着/肌动蛋白细胞骨架信号转录物以及调节脂肪形成的基因的诱导发生了重大变化。我们提出类似的机制是负责老年小鼠骨骼肌脂肪沉积的积累，syndecan-4和syndecan-3缺失小鼠，我们提出卫星细胞需要一个环境生态位来维持肌源性身份和承诺肌源性分化。这个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选择不同的分化途径。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）鉴定体内脂肪积累的细胞群，以及（iii）评估已鉴定因素在调节培养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 Recent published and unpublished work from our laboratory shows that uninjured muscle from syndecan-3 null and syndecan-4 null mice contain excess fat deposition.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.