Gut microbiota-derived 3-indolepropionic acid attenuates obesity-associated muscle dysfunction by restoring mitochondrial homeostasis via the GSR-DRP1/OPA1 axis

This is the authors' abstract. We don't add key points for this paper.

Obesity-associated muscle dysfunction is often overlooked. Gut-derived metabolites can modulate metabolic homeostasis and muscle function through multiple pathways. However, the specific metabolites that play a critical role in obesity-associated muscle dysfunction, as well as their therapeutic potential, remain insufficiently characterised. In this study, the high-fat diet (HFD)-fed rat model was established to investigate the contribution of gut microbial metabolites to obesity-associated muscle dysfunction. Integrated analyses using 16S rRNA gene sequencing and targeted metabolomics identified a reduced abundance of indole-3-propionic acid (IPA), a key metabolite in tryptophan metabolism, as being closely associated with the development of obesity-associated muscle dysfunction. IPA supplementation markedly ameliorated HFD-induced intestinal barrier disruption, muscle dysfunction, and intramuscular lipid infiltration. Through multimodal machine learning and network pharmacology analyses, GSR-mediated regulation of mitochondrial dynamics may underlie the protective effects of IPA. Molecular docking and molecular dynamics simulations indicated favourable binding between IPA and GSR, dynamin-related protein 1 (DRP1), and optic atrophy protein 1 (OPA1). In vivo experiments showed that IPA reduced lipopolysaccharide (LPS) levels associated with intestinal barrier dysfunction. This reduction was accompanied by increased GSR activity and restoration of mitochondrial dynamics-related protein expression. In vitro experiments showed that IPA restored GSR activity after inhibition with a GSR-specific inhibitor. Collectively, these findings indicate that IPA exerts muscle-protective effects through restoration of intestinal barrier integrity and reestablishment of mitochondrial homeostasis. This study provides a scientific basis for precision nutrition strategies targeting obesity-associated muscle dysfunction.