Nakamura Katsuyuki, Nakano Shin-Ichi, Miyoshi Takahiro, Yamanouchi Keitaro, Matsuwaki Takashi, Nishihara Masugi
Department of Veterinary Physiology, Graduate School of Agricultural and Life Sciences, The University of Tokyo, 1-1-1 Yayoi, Bunkyo-ku, Tokyo 113-8657, Japan.
Aging (Albany NY). 2012 Jan;4(1):40-8. doi: 10.18632/aging.100426.
Aging causes phenotypic changes in skeletal muscle progenitor cells (SMPCs) that lead to the loss of myogenicity and adipogenesis. Secreted protein acidic and rich in cysteine (SPARC), which is secreted from SMPCs, stimulates myogenesis and inhibits adipogenesis. The present study aimed to examine whether changes in SPARC expression, its signaling pathway, or both are involved in age-related phenotypic changes in SMPCs. SPARC expression levels were comparable in SMPCs derived from young and old rats. However, when SPARC expression was reduced by a SPARC-specific siRNA, SMPCs from young rats showed reduced myogenesis and increased adipogenesis. In striking contrast, old rats showed little changes in these functions. Recombinant SPARC was effective in inhibiting adipogenesis and promoting myogenesis of SMPCs from young rats but had no effect on SMPCs from old rats when endogenous SPARC levels were reduced by the SPARC-siRNA. Further, the level of integrin α5, a subunit of the putative SPARC receptor, was decreased in SMPCs from old rats, and its inhibition in SMPCs from young rats by siRNA reduced adipogenesis in response to SPARC. These results suggest that, although SPARC plays a role in regulating SMPC function, SMPCs become refractory to the action of SPARC with age. Our data may explain an age-related shift from myogenesis to adipogenesis, associated with sarcopenia.
衰老会导致骨骼肌祖细胞（SMPCs）发生表型变化，进而导致肌生成和脂肪生成能力丧失。SMPCs分泌的富含半胱氨酸的酸性分泌蛋白（SPARC）可刺激肌生成并抑制脂肪生成。本研究旨在探讨SPARC表达的变化、其信号通路的变化或两者是否参与了SMPCs与年龄相关的表型变化。来自年轻和老年大鼠的SMPCs中SPARC表达水平相当。然而，当用SPARC特异性小干扰RNA（siRNA）降低SPARC表达时，来自年轻大鼠的SMPCs肌生成减少，脂肪生成增加。与之形成鲜明对比的是，老年大鼠在这些功能上几乎没有变化。当通过SPARC-siRNA降低内源性SPARC水平时，重组SPARC可有效抑制来自年轻大鼠的SMPCs的脂肪生成并促进其肌生成，但对来自老年大鼠的SMPCs没有影响。此外，整合素α5（推测的SPARC受体的一个亚基）的水平在来自老年大鼠的SMPCs中降低，并且通过siRNA抑制来自年轻大鼠的SMPCs中的整合素α5会降低对SPARC的脂肪生成反应。这些结果表明，尽管SPARC在调节SMPC功能中起作用，但随着年龄的增长，SMPCs对SPARC的作用变得不敏感。我们的数据可能解释了与肌肉减少症相关的从肌生成到脂肪生成的年龄相关转变。
