Aug 2026· Metabolism: Clinical and Experimental· 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.
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Abstract 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 dyshomeostasis 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.
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