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Background <p>Follistatin is a potent regulator of various TGF-β superfamily members, including myostatin (MSTN) and activin A. Previous studies have shown that follistatin is crucial in enhancing myogenesis during acute muscle injury. The mechanism by which fibro-adipogenic progenitors (FAPs)-specific follistatin influences muscle homeostasis in obese mice remains unknown. Therefore, we investigated the physiological role of follistatin in PDGFRα-positive FAPs in the regulation of muscle homeostasis and exercise in obese mice.</p> Methods <p>A PDGFRα-specific follistatin knockout (follistatin KO) mouse model was generated using PDGFRα-GFP-CreER<sup>T2</sup> (PDGFRα-GCE) and follistatin<sup>flox/flox</sup> mice. These mice were fed a 60% high-fat diet (HFD) for 20&#xa0;weeks, followed by a series of analyses, including exercise tolerance test, grip strength test, glucose and insulin tolerance assays, gene expression analysis, histology, western blotting, and immunohistochemistry.</p> Results <p>We showed that follistatin KO mice had reduced expression of <i>Fst</i> in skeletal muscle and white adipose tissue. We also showed that follistatin KO mice exhibited decreased exercise performance and altered skeletal homeostasis during obesity. Deletion of follistatin in FAPs activated the MSTN: Activin A/SMADs signaling pathways, which negatively impacted muscle homeostasis. Furthermore, follistatin KO mice showed reduced muscle mass, increased muscle degradation, and atrophic myofibers. Mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation were also altered in the skeletal muscles of follistatin KO mice.</p> Conclusion <p>Follistatin plays a protective role in mice by maintaining the metabolic health of skeletal muscles; it restores muscle function during HFD challenge, thereby reducing diet-induced obesity-related complications.</p> Graphical Abstract <p></p>

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Deletion of fibro-adipogenic progenitors-specific follistatin impairs muscle function and accelerates skeletal muscle atrophy in obese mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月21日

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  • Muhammad Rahil Aslam,
  • Muhammad Bilal,
  • Allah Nawaz,
  • Tomonobu Kado,
  • Shinya Abe,
  • Nguyen Quynh Phuong,
  • Memoona,
  • Sana Khalid,
  • Le Duc Anh,
  • Ayumi Nishimura,
  • Yoshiyuki Watanabe,
  • Yoshiko Igarashi,
  • Naeem Iqbal,
  • Maki Yokoyama,
  • Yasuhiro Onogi,
  • Kennichi Hirabayashi,
  • Hiroyuki  Miwa,
  • Takumi Era,
  • Martin M. Matzuk,
  • Seiji Yamamoto,
  • Koichi Ikuta,
  • Isao Usui,
  • Kohta Kobayashi,
  • Toshihiko Satake,
  • Masaru Kato,
  • Shiho Fujisaka,
  • Kazuyuki Tobe

摘要

Background

Follistatin is a potent regulator of various TGF-β superfamily members, including myostatin (MSTN) and activin A. Previous studies have shown that follistatin is crucial in enhancing myogenesis during acute muscle injury. The mechanism by which fibro-adipogenic progenitors (FAPs)-specific follistatin influences muscle homeostasis in obese mice remains unknown. Therefore, we investigated the physiological role of follistatin in PDGFRα-positive FAPs in the regulation of muscle homeostasis and exercise in obese mice.

Methods

A PDGFRα-specific follistatin knockout (follistatin KO) mouse model was generated using PDGFRα-GFP-CreERT2 (PDGFRα-GCE) and follistatinflox/flox mice. These mice were fed a 60% high-fat diet (HFD) for 20 weeks, followed by a series of analyses, including exercise tolerance test, grip strength test, glucose and insulin tolerance assays, gene expression analysis, histology, western blotting, and immunohistochemistry.

Results

We showed that follistatin KO mice had reduced expression of Fst in skeletal muscle and white adipose tissue. We also showed that follistatin KO mice exhibited decreased exercise performance and altered skeletal homeostasis during obesity. Deletion of follistatin in FAPs activated the MSTN: Activin A/SMADs signaling pathways, which negatively impacted muscle homeostasis. Furthermore, follistatin KO mice showed reduced muscle mass, increased muscle degradation, and atrophic myofibers. Mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation were also altered in the skeletal muscles of follistatin KO mice.

Conclusion

Follistatin plays a protective role in mice by maintaining the metabolic health of skeletal muscles; it restores muscle function during HFD challenge, thereby reducing diet-induced obesity-related complications.

Graphical Abstract