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

PLoS One. 2019 Aug 23;14(8):e0221366. doi: 10.1371/journal.pone.0221366. eCollection 2019.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism*
  • Adipose Tissue / pathology
  • Aging / genetics
  • Aging / metabolism
  • Aging / pathology
  • Animals
  • Cellular Senescence / genetics
  • Disease Models, Animal
  • Forkhead Box Protein O1 / genetics
  • Humans
  • Mice
  • Mice, Obese
  • Muscle Proteins / genetics
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / pathology
  • Muscular Atrophy / genetics*
  • Muscular Atrophy / metabolism
  • Muscular Atrophy / pathology
  • Obesity / genetics*
  • Obesity / metabolism
  • Obesity / pathology
  • Quality of Life
  • SKP Cullin F-Box Protein Ligases / genetics
  • Sarcopenia / genetics*
  • Sarcopenia / metabolism
  • Sarcopenia / pathology
  • Tripartite Motif Proteins / genetics
  • Ubiquitin-Protein Ligases / genetics

Substances

  • Forkhead Box Protein O1
  • Foxo1 protein, mouse
  • Muscle Proteins
  • Tripartite Motif Proteins
  • Fbxo32 protein, mouse
  • SKP Cullin F-Box Protein Ligases
  • Trim63 protein, mouse
  • Ubiquitin-Protein Ligases

Grant support

This work was supported by the Japan Society for the Promotion of Science, Grant 17H05652 (to Y. O.), the Core Research for Evolutional Science and Technology (CREST) Program of the Japan Science and Technology Agency (JST) Grant 13417915 (to Y. O.), the CREST Program of the Japan Agency for Medical Research and Development (AMED) Grant 18gm0610007 (to Y. O.), and by the Project for Elucidating and Controlling Mechanisms of Aging and Longevity from AMED Grant 17gm5010002 (to Y. O.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.