{
  "abstract": "Type 2 diabetes mellitus (T2DM)-associated sarcopenia is driven by protein degradation and impaired myogenic regeneration. While classical models emphasize cytosolic kinase pathways, the subcellular mechanisms mediating lipotoxicity-induced chronic catabolism remain incompletely understood. This review elucidates a tripartite pathological cascade comprising organelle structural uncoupling, metabolic intermediate overflow, and epigenetic reprogramming. Chronic intramyocellular lipid accumulation disrupts lipid droplet–mitochondria contact (LDMC) sites, largely via Mfn2 modification. This spatial dissociation impairs mitochondrial oxidation, driving the nucleocytoplasmic accumulation of polar metabolites, specifically Acetyl-CoA, succinate, and lactate. Acting as covalent substrates or competitive inhibitors, these metabolites modulate histone-modifying enzymes such as p300/CBP and JmjC-domain demethylases. Consequently, this substrate-driven epigenetic remodeling increases chromatin accessibility at E3 ubiquitin ligase promoters ( Atrogin-1 , MuRF1 ) and concurrently represses myogenic loci ( MyoD , MyoG ), locking the tissue in a catabolic transcriptional state. Effective interventions must target this organelle-metabolite-epigenetic axis. Beyond systemic agents like SGLT2 inhibitors and GLP-1 receptor agonists, precision strategies—including repairing LDMC topology, bypassing enzymatic bottlenecks via CPT1 or LDHA, and restoring epigenetic homeostasis—are necessary to preserve lean mass and maintain skeletal muscle under metabolic stress.",
  "abstract_shown": true,
  "affiliations": [
    "School of Acupuncture-Moxibustion and Tuina, Changchun University of Chinese Medicine",
    "Department of Pain Management, Affiliated Hospital of Changchun University of Chinese Medicine",
    "Department of Nephrology, Affiliated Hospital of Changchun University of Chinese Medicine",
    "Department of Acupuncture and Moxibustion, Affiliated Hospital of Changchun University of Chinese Medicine"
  ],
  "article_type": "review article",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Lingfeng Wu"
    },
    {
      "affs": [
        1
      ],
      "name": "Ye Wang"
    },
    {
      "affs": [
        2
      ],
      "name": "Kailian Ma"
    },
    {
      "affs": [
        3
      ],
      "name": "Yang Liu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/4xkmz9eskca68.bib",
  "cited_by": 0,
  "doi": "10.3389/fendo.2026.1980958",
  "fulltext_url": "https://europepmc.org/articles/PMC13711501",
  "id": "4xkmz9eskca68",
  "issns": [
    "1664-2392"
  ],
  "landing_url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1980958/full",
  "language": "eng",
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Review"
    ],
    [
      "openalex",
      "1312|Muscle Physiology and Disorders"
    ]
  ],
  "openalex": "W7221632931",
  "pdf_url": "https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2026.1980958/pdf",
  "pmcid": "PMC13711501",
  "pmid": "42948624",
  "published": "2026-10-13",
  "publisher": "Frontiers Media SA",
  "ris": "https://research.draconitic.com/paper/4xkmz9eskca68.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:20:20Z",
      "native_id": "10.3389/fendo.2026.1980958",
      "source": "crossref",
      "url": "https://www.frontiersin.org/articles/10.3389/fendo.2026.1980958/full"
    },
    {
      "first_seen": "2026-10-31T00:20:34Z",
      "native_id": "MED:42948624",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42948624"
    },
    {
      "first_seen": "2026-10-31T12:22:16Z",
      "native_id": "PMC13711501",
      "source": "pmc",
      "url": "https://doi.org/10.3389/fendo.2026.1980958"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Muscle Physiology and Disorders",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Intramyocellular lipid droplet–mitochondria uncoupling drives muscle atrophy via metabolite-directed epigenetic reprogramming: a review",
  "title_text": "Intramyocellular lipid droplet–mitochondria uncoupling drives muscle atrophy via metabolite-directed epigenetic reprogramming: a review",
  "type": "peer-reviewed",
  "updated_at": "2026-10-31T12:22:16Z",
  "url": "https://research.draconitic.com/paper/4xkmz9eskca68",
  "venue": "Frontiers in Endocrinology",
  "versions": []
}