Age-related Changes in a Myogenic Niche

描述(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影响。最近针对老龄化人口肌肉质量和肌肉功能丧失的临床研究得出结论，脂肪的摄入是导致年龄相关性石棺减少的重要因素(Goodpastertal，2001；Pahorand Kritchevsky，1998；Sowers Etal.，2005)。导致骨骼肌脂肪堆积增加的细胞来源尚不清楚。然而，大量的轶事证据表明，骨骼肌卫星细胞可能参与了这一过程。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护和修复，具有干细胞样特性(Hawke和Garry，2001；Schultz和McCormick，1994；Seale等人，2001；Seale和Rudicki，2000；Wagers和Conball，2005)，并能够在培养中向成骨和成脂分化(Wada et al.，2002)。从老年啮齿动物培养的卫星细胞获得成脂表型(Taylor-Jones等人，2002年)。我们实验室最近发表和未发表的工作表明，syndecan-3基因缺失和syndecan-4基因缺失小鼠的未损伤肌肉含有过量脂肪沉积。此外，来自这些小鼠的卫星细胞在培养中无法与Syndecan-4零细胞分化，显示出同时促进脂肪生成(Cornelison等人，2004年)。Syndecans是环境信息和细胞黏附的关键媒介，非常适合识别局部微环境(Tkachenko等人，2005年)。有趣的是，微阵列数据将Syndecan-3和Syndecan-4缺失的卫星细胞与wt细胞进行比较，发现焦点阿德金/肌动蛋白细胞骨架信号转录本以及调控脂肪形成的基因的诱导发生了重大变化。我们认为，类似的机制是导致衰老的wt小鼠、syndecan-4基因缺失和syndecan-3基因缺失的小鼠骨骼肌中脂肪沉积的原因，在这些小鼠中，卫星细胞需要一个环境生态位来维持成肌身份和对成肌分化的承诺。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另一条分化途径。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)确定在体内导致脂肪积累的细胞群，以及(Iii)评估已确定的因素在调节培养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 Recent published and unpublished work from our laboratory shows that uninjured muscle from syndecan-3 null and syndecan-4 null mice contain excess fat deposition.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.