Tier 3 — preclinical

Alpha-ketoglutarate ameliorates diabetes-associated skeletal muscle fibrosis by restoring TET2-dependent epigenetic remodeling in CD90 positive fibro-adipogenic progenitors

Tong ZJ, Li YH, Song M, Sheng YN, Wu YZ, Shang YY, Hu BA, Lu B, Zhu P, Wang GQ, Zhan HJ, Han L, Zhang W, Wang ZH, Zhong M
Metabolism 2026 184:156731

Bibliography

PubMed
PMID 42575166
DOI
10.1016/j.metabol.2026.156731
Funding
Funded by Taishan Scholars (tsqn202103146); National Natural Science Foundation of China (82500544, 82070392, 81702194, 81801953); Natural Science Foundation of Shandong Province (ZR2023MH075, ZR2021QH033, ZR2022QH302); Key Research and Development Program of Shandong Province (2024TSGC0089, 2019GSF108041); Shandong Postdoctoral Science Foundation (SDZZ-ZR-20251052); China International Medical Foundation (Z-2017-26-2202-4); and China Heart House–Chinese Cardiovascular funding reported by the publisher.
Competing interests
The authors declared no known competing financial interests or personal relationships that could have appeared to influence the work.

Study snapshot

DesignTranslational human-tissue, cellular and diabetic-mouse mechanistic study.
ModelHuman skeletal-muscle observations plus T2DM mouse and fibro-adipogenic progenitor experiments.
SampleMultiple human and preclinical cohorts; intervention group size varies by experiment.
InterventionDietary alpha-ketoglutarate supplementation in T2DM mice; mechanistic TET2 perturbation in FAPs.
DurationStudy-specific diabetic mouse supplementation and cell experiments.
EndpointsSkeletal-muscle fibrosis; αKG/L-2HG ratio; DNA hydroxymethylation; TET2 activity; Fibro-adipogenic progenitor polarity; Profibrotic activation

What the study showed, in plain terms

This 2026 study links altered AKG metabolism to skeletal-muscle fibrosis in type 2 diabetes.

Dietary AKG restored the AKG/L-2HG ratio and reduced muscle fibrosis in diabetic mice through a TET2-dependent epigenetic mechanism. Human tissue data helped establish the disease-associated pathway, but humans were not supplemented with AKG.

The paper strengthens mechanistic muscle evidence while remaining preclinical for oral Ca-AKG efficacy.

Key findings

  • Dietary AKG reduced skeletal-muscle fibrosis in T2DM mice.
  • The effect depended in part on TET2-driven DNA hydroxymethylation.
  • Human diabetic muscle data supported the relevance of the AKG/L-2HG-TET2 pathway, but not supplement efficacy.

What this study can and cannot tell us

  • The supplementation intervention was performed in mice, not humans.
  • The disease context is type 2 diabetes-associated fibrosis rather than age-related sarcopenia in otherwise healthy adults.
  • No commercial Ca-AKG formulation was tested.

Citation network

Articles citing this research paper

1 article

Biohack Blueprint analyses that reference this study in their evidence base.

Editorial review

Reviewed by the Biohack Blueprint research team

Last verified

Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology