Aug 2026· Metabolism: Clinical and Experimental· Vol 184, pp.
156731
· 1 citation· 46 references
Medicine
TL;DR
Dysregulation of α-KG and L-2HG drives diabetic muscle fibrosis by disrupting TET2-dependent DNA hydroxymethylation and FAP division symmetry, supporting a TET2-dependent mechanism underlying the epigenetic effects of α-KG.
Abstract
Objective
Fibro-adipogenic progenitor (FAP) dysfunction drives skeletal muscle fibrosis in type 2 diabetes mellitus (T2DM), yet the underlying metabolic-epigenetic mechanisms remain poorly understood. This study investigates how metabolite fluctuations regulate the cell fate of CD90+ FAPs in the diabetic skeletal muscles.
Methods
AND
Results
Re-analysis of single-cell RNA sequencing data from human diabetic skeletal muscle, combined with immunofluorescence staining of biopsy specimens, revealed a significant expansion of CD90+ FAPs characterized by aberrant asymmetric cell division (ACD) associated polarity and a profibrotic phenotype. Using LC-MS, we identified a marked metabolic shift in insulin-resistant CD90+ FAPs, with reduced alpha-ketoglutarate (α-KG) and elevated L-2-hydroxyglutarate (L-2HG) levels. Reduced α-KG availability, together with competitive inhibition by accumulated L-2HG, suppresses TET2 activity and shifts DNA cytosine modification toward increased 5mC and decreased 5hmC. Specifically, epigenetic remodeling at the promoters of polarity-related genes-Pard3b, Pard6b, and Prkcz-was associated with activation of an ACD-related polarity program in CD90+ FAPs. This lineage bias promotes fibrogenic differentiation, ultimately exacerbating collagen accumulation and impairing muscle function. Dietary α-KG supplementation restored the α-KG/L-2HG ratio, restrained aberrant ACD-related polarity program, and effectively prevented or alleviated muscle fibrosis in T2DM mice. Conversely, TET2 knockdown attenuated the protective effects of α-KG on DNA hydroxymethylation and profibrotic activation of CD90+ FAPs, supporting a TET2-dependent mechanism underlying the epigenetic effects of α-KG.
Conclusion
Our findings demonstrate that dysregulation of α-KG and L-2HG drives diabetic muscle fibrosis by disrupting TET2-dependent DNA hydroxymethylation and FAP division symmetry. Restoring this metabolic-epigenetic axis represents a promising therapeutic strategy for treating diabetic skeletal muscle fibrosis.
It is shown that dysregulated endocrine function of skeletal muscle promotes bone loss through YAP1-driven pathogenic FAPs secreting IL-6 and FGF21, identifying FAP-derived IL-6 and FGF21 as key mediators of muscle-bone crosstalk and establishing the YAP-FAP-myokine axis as a therapeutic target for preventing bone loss in sarcopenia and osteoporosis.
Xiaoyu Cai, Tao Xu, R. Ma et al.· Advancement of science· 0 citations
Age‐related sarcopenia is characterized by a progressive decline in skeletal muscle mass and function, with satellite cell dysfunction representing a central pathogenic mechanism. Diosgenin, a steroidal saponin derived from plants of the Dioscorea genus, has demonstrated potential anti‐aging properties; however, its role in sarcopenia remains unclear. In this study, naturally aged C57BL/6J mice and a D‐galactose (D‐gal)–induced senescent C2C12 cell model were employed to systematically investigate the effects of diosgenin on muscle function, satellite cell dynamics, and the sirtuin 1 (SIRT1)/peroxisome proliferator‐activated receptor gamma coactivator‐1 alpha (PGC‐1α) signaling pathway. Diosgenin treatment significantly improved forelimb grip strength and exercise endurance, increased the gastrocnemius muscle index, and enlarged muscle fiber cross‐sectional area in aged mice. Mechanistically, diosgenin upregulated the expression of myokines meteorin‐like protein (METRNL) and insulin‐like growth factor 1 (IGF‐1) at both mRNA and protein levels, increased the number of proliferative satellite cells positive for paired box 7 (Pax7) and Ki67, and enhanced the expression of myogenic markers, including myogenic factor 5 (Myf5), Pax7, and myosin heavy chain II (MyHC II). These effects were mediated by direct activation of SIRT1, leading to deacetylation of PGC‐1α. Notably, pharmacological inhibition of SIRT1 with EX527 markedly abrogated the diosgenin‐induced effects. Molecular docking and cellular thermal shift assays further confirmed the direct interaction between diosgenin and SIRT1. Collectively, these findings demonstrate that diosgenin alleviates age‐related sarcopenia by activating the SIRT1/PGC‐1α signaling pathway to promote satellite cell proliferation and myogenic differentiation, highlighting its potential as a promising therapeutic candidate for sarcopenia.
Xin Zeng, Han-Wen Ding, Ziye Li et al.· Aging Cell· 0 citations
Age-related sarcopenia is a progressive skeletal muscle disorder driven by oxidative stress and metabolic dysregulation. Cu/Zn superoxide dismutase-deficient (Sod1-/-) mice recapitulate key features of oxidative stress-induced muscle degeneration and provide a robust preclinical model for mechanistic and therapeutic studies. Here, we investigated whether systemic administration of human umbilical cord-derived mesenchymal stem cells (UC-MSCs) could modulate muscle function and metabolic homeostasis under both pathological and physiological conditions. In Sod1-/- mice, UC-MSC treatment significantly improved motor coordination and grip endurance, restored gastrocnemius myofiber number, markedly reduced mitochondrial reactive oxygen species production and catalase expression levels in skeletal muscle, and restored muscle ATP content. UC-MSCs also restored circulating insulin-like growth factor-1 (IGF-1) levels. Untargeted lipidomic profiling revealed profound depletion of lipid species in Sod1-/- muscle, particularly omega-3 fatty acids, which was selectively rescued by UC-MSC therapy, including restoration of α-linolenic acid, eicosapentaenoic acid, and docosahexaenoic acid, without substantial recovery of disrupted polar metabolic pathways such as aminoacyl-tRNA biosynthesis. In contrast, UC-MSC administration in wild-type mice induced a distinct metabolic remodeling characterized by reduced n-3 and n-6 fatty acid-associated lipid species and concomitant enrichment of fructose-related glycolytic intermediates, indicating a shift toward carbohydrate-based energy utilization in metabolically intact muscle. Together, these findings demonstrate that UC-MSCs function as context-dependent metabolic modulators, alleviating oxidative stress-induced sarcopenia through attenuation of oxidative stress, restoration of systemic IGF-1, and selective reprogramming of lipid metabolism, while dynamically adjusting energy metabolism in physiological skeletal muscle.
: Type 2 diabetes mellitus (T2DM)-associated sarcopenia extends beyond isolated metabolic dysregulation; consequently, standard glucose-centric therapeutic strategies are insufficient to arrest myofibrillar atrophy. In this review, we characterize this pathogenesis through a novel spatial-bioenergetic-immune axis, stratifying disease progression across three hierarchical levels. First, within the tissue niche, the proliferation of CD90 + fibro-adipogenic progenitors (FAPs) establishes a pro-inflammatory microenvironment, driving extracellular matrix fibrosis that physically constrains the myogenic niche. Second, at the subcellular organelle level, kinase-driven structural disruption of mitochondria-associated endoplasmic reticulum membranes (MAMs) induces calcium dysho-meostasis and oxidative stress, culminating in bioenergetic collapse and NLRP3 inflammasome assembly. Third, at the immune-nuclear axis, retrograde signaling—exacerbated by GSDMD-mediated sarcolemmal permeabilization—induces sustained transcriptional repression of core myogenic programs. Synthesizing these spatial mechanisms, we propose a comprehensive clinical paradigm. By integrating microenvironmental modulation (SGLT2 inhibitors/GLP-1RAs), structural mechanotransduction (HIIT), and epigenetic rejuvenation (15-PGDH inhibitors), we advocate for a transition toward precision clinical management of T2DM-associated sarcopenia, aimed at arresting skeletal muscle degeneration and preserving physical functional capacity.
Lingfeng Wu, Hong Ye, Xiao-Feng Wang et al.· Journal of Inflammation Rese...· 0 citations
Duchenne muscular dystrophy (DMD) is a severe and progressive form of muscular dystrophy caused by mutations in the dystrophin gene. We previously observed that loss of dystrophin in human induced pluripotent stem cell–derived cardiac fibroblasts (hiPSC-cFib) dysregulated the actin network and induced a metabolic remodeling associated with an exacerbated myofibroblast phenotype. The endocannabinoid signaling (ECS) system plays an important role in chronic inflammatory and fibrotic conditions and is dysregulated in skeletal muscle of DMD patients. Here, we investigated the effects of cannabidiol (CBD) on hiPSC-cFib from healthy controls and DMD patients. CBD failed to modify metabolic responses in DMD hiPSC-cFib, while significantly promoting glycolysis and cell proliferation in control hiPSC-cFib. Despite these distinct metabolic responses, CBD significantly attenuated TGF-β–induced myofibroblast activation in both DMD and control hiPSC-cFib by lowering α-smooth muscle actin and collagen type I levels suggesting a metabolism-independent mechanism. Additionally, CBD exerted strong antioxidant effects on both DMD and control hiPSC-cFib, markedly reducing intracellular reactive oxygen species (ROS) levels, increasing GSH levels and robustly inducing heme oxygenase-1 (HO-1) expression in a time- and dose-dependent manner which could not be mimicked by CB1R or CB2R agonists and blocked by their antagonists. Pharmacological inhibition of HO-1 blunted CBD's ability to suppress TGF-β–induced activation of DMD and control hiPSC-cFib, demonstrating that HO-1 is a key mediator of CBD's anti-fibrotic action. Together, these findings showed stimulation of glycolytic metabolism by CBD, regulation which is lost in DMD hiPSC-cFib. We uncovered a previously unrecognized HO-1–dependent pathway by which CBD dampens profibrotic activation in human DMD and control hiPSC-cFib, highlighting its potential as a therapeutic approach to limit cardiac fibrosis in Duchenne muscular dystrophy.
L. Savchenko, S. Soussi, D. Rovina et al.· Redox Biology· 0 citations
It is demonstrated that TMZ mitigates dystrophic pathology by targeting the ATP6AP2 signaling axis and dampening macrophage-mediated inflammatory responses, highlighting its potential as a novel immunopharmacological therapeutic strategy for DMD.
Lin Zhou, Yu Zhang, Xinxin Tan et al.· International Immunopharmaco...· 0 citations
