Aging- and obesity-related peri-muscular adipose tissue accelerates muscle atrophy

Sarcopenia due to loss of skeletal muscle mass and strength leads to physical inactivity and decreased quality of life. The number of individuals with sarcopenia is rapidly increasing as the number of older people increases worldwide, making this condition a medical and social problem. Some patients with sarcopenia exhibit accumulation of peri-muscular adipose tissue (PMAT) as ectopic fat deposition surrounding atrophied muscle. However, an association of PMAT with muscle atrophy has not been demonstrated. Here, we show that PMAT is associated with muscle atrophy in aged mice and that atrophy severity increases in parallel with cumulative doses of PMAT. We observed severe muscle atrophy in two different obese model mice harboring significant PMAT relative to respective control non-obese mice. We also report that denervation-induced muscle atrophy was accelerated in non-obese young mice transplanted around skeletal muscle with obese adipose tissue relative to controls transplanted with non-obese adipose tissue. Notably, transplantation of obese adipose tissue into peri-muscular regions increased nuclear translocation of FoxO transcription factors and upregulated expression FoxO targets associated with proteolysis (Atrogin1 and MuRF1) and cellular senescence (p19 and p21) in muscle. Conversely, in obese mice, PMAT removal attenuated denervation-induced muscle atrophy and suppressed upregulation of genes related to proteolysis and cellular senescence in muscle. We conclude that PMAT accumulation accelerates age- and obesity-induced muscle atrophy by increasing proteolysis and cellular senescence in muscle.

因骨骼肌质量与肌力流失引发的肌肉减少症（Sarcopenia），会导致机体活动能力减退及生活质量下降。随着全球老年人口规模持续扩张，肌肉减少症患者数量正快速攀升，该病症已成为一项亟待解决的医学与社会公共问题。
部分肌肉减少症患者的萎缩肌肉周围会出现异位脂肪沉积，即肌周脂肪组织（peri-muscular adipose tissue，PMAT）堆积。然而，目前尚未明确PMAT与肌肉萎缩之间的关联机制。
本研究证实，老年小鼠体内的PMAT水平与肌肉萎缩程度呈正相关，且萎缩严重程度随PMAT累积剂量的增加而同步升高。相较于各自对应的非肥胖对照小鼠，我们在两种存在显著PMAT堆积的肥胖模型小鼠体内均观察到了严重的肌肉萎缩现象。
此外我们发现，相较于移植非肥胖脂肪组织的对照小鼠，在骨骼肌周围移植肥胖脂肪组织的非肥胖年轻小鼠，其失神经支配诱导的肌肉萎缩进程显著加快。
值得注意的是，将肥胖脂肪组织移植至肌周区域后，小鼠肌肉内的FoxO转录因子核转位水平显著升高，且与蛋白水解（肌肉萎缩盒1（Atrogin1）、肌肉环指蛋白1（MuRF1））及细胞衰老（p19、p21）相关的FoxO靶基因表达均被上调。
反之，在肥胖小鼠体内清除PMAT后，其失神经支配诱导的肌肉萎缩症状得到缓解，且肌肉内与蛋白水解及细胞衰老相关的基因上调表达被显著抑制。
综上，我们认为PMAT堆积通过增强肌肉内的蛋白水解过程与细胞衰老进程，加速了衰老及肥胖诱导的肌肉萎缩。