Deletion of Fibro-Adipogenic Progenitors-Specific Follistatin Impairs Muscle Function and Accelerates Skeletal Muscle Atrophy in Obese Mice

Authors

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

Publication Date

11-21-2025

Journal

Molecular Medicine

DOI

10.1186/s10020-025-01393-1

PMID

41272451

Abstract

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.

Keywords

Exercise capacity. Fibro-adipogenic progenitors (FAPs). Follistatin. Muscle mass. Obesity

Published Open-Access

yes

Recommended Citation

Aslam, Muhammad Rahil; Bilal, Muhammad; Nawaz, Allah; et al., "Deletion of Fibro-Adipogenic Progenitors-Specific Follistatin Impairs Muscle Function and Accelerates Skeletal Muscle Atrophy in Obese Mice" (2025). Faculty and Staff Publications. 5136.
https://digitalcommons.library.tmc.edu/baylor_docs/5136