Study summary · research use only
Deletion of fibro-adipogenic progenitors-specific follistatin impairs muscle function and accelerates skeletal muscle atrophy in obese mice
Plain-language summary
Paraphrased from the published abstract below — not a verdict on whether anything works.
In this mouse study, researchers generated a PDGFRα-specific follistatin knockout mouse model and fed these mice and controls a 60% high-fat diet for 20 weeks, then assessed exercise tolerance, grip strength, glucose and insulin tolerance, gene expression, histology, and protein levels. Follistatin knockout mice showed reduced Fst expression in skeletal muscle and white adipose tissue, decreased exercise performance, and altered skeletal muscle homeostasis during obesity. Deletion of follistatin in fibro-adipogenic progenitors activated MSTN/Activin A/SMADs signaling, and knockout mice had reduced muscle mass, increased muscle degradation, atrophic myofibers, and altered mitochondrial biogenesis, oxidative phosphorylation, and fatty acid oxidation in skeletal muscle. The authors describe follistatin as involved in maintaining metabolic health of skeletal muscle and restoring muscle function under high-fat-diet challenge.
Abstract
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. 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. 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. 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.
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