Brown Adipose Tissue Controls Skeletal Muscle Function via the Secretion of Myostatin

Cell Metab. 2018 Oct 2;28(4):631-643.e3. doi: 10.1016/j.cmet.2018.07.004. Epub 2018 Aug 2.


Skeletal muscle and brown adipose tissue (BAT) are functionally linked, as exercise increases browning via secretion of myokines. It is unknown whether BAT affects muscle function. Here, we find that loss of the transcription factor IRF4 in BAT (BATI4KO) reduces exercise capacity, mitochondrial function, ribosomal protein synthesis, and mTOR signaling in muscle and causes tubular aggregate formation. Loss of IRF4 induces myogenic gene expression in BAT, including the secreted factor myostatin, a known inhibitor of muscle function. Reducing myostatin via neutralizing antibodies or soluble receptor rescues the exercise capacity of BATI4KO mice. In addition, overexpression of IRF4 in brown adipocytes reduces serum myostatin and increases exercise capacity in muscle. Finally, mice housed at thermoneutrality have reduced IRF4 in BAT, lower exercise capacity, and elevated serum myostatin; these abnormalities are corrected by excising BAT. Collectively, our data point to an unsuspected level of BAT-muscle crosstalk driven by IRF4 and myostatin.

Keywords: IRF4; brown adipose tissue; exercise; myopathy; myostatin; thermoneutrality; tubular aggregates.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipocytes, Brown / metabolism
  • Adipose Tissue, Brown / metabolism*
  • Animals
  • Antibodies, Neutralizing / metabolism
  • Energy Metabolism / physiology
  • Gene Expression Regulation
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microscopy, Electron
  • Mitochondria / metabolism
  • Muscular Diseases / diagnostic imaging
  • Muscular Diseases / metabolism
  • Myostatin / genetics
  • Myostatin / metabolism*
  • Oxygen Consumption
  • Physical Conditioning, Animal / physiology*
  • Quadriceps Muscle / diagnostic imaging
  • Quadriceps Muscle / metabolism*
  • Thermosensing / physiology
  • Transforming Growth Factor beta / metabolism


  • Antibodies, Neutralizing
  • Interferon Regulatory Factors
  • Mstn protein, mouse
  • Myostatin
  • Transforming Growth Factor beta
  • interferon regulatory factor-4