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<p>Type 2 diabetes mellitus (T2DM) complicated by muscle atrophy (diabetic sarcopenia) significantly increases mortality risk, with immunometabolic imbalance-driven disruption of the skeletal muscle microenvironment as a core mechanism. This review focuses on the immune cell–myocyte crosstalk network to elucidate the pathological mechanisms of T2DM-induced muscle atrophy, the local remodeling effects of exercise, and systemic organ crosstalk. In the T2DM state, M1/M2 imbalance and metabolic reprogramming of macrophages, dysregulated mast cell activation and histamine signaling, NLRP3 inflammasome-mediated pyroptosis, T-cell immunosenescence, and chemokine storms collectively disrupt muscle homeostasis. Exercise reverses these abnormalities by downregulating TRIB3/AKT to promote M2 polarization, restoring mast cell function, inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway, increasing Treg infiltration, and downregulating the chemokine network, thereby shifting the local microenvironment from a “pro-inflammatory/destructive” to a “reparative/regenerative” state. Furthermore, exercise exerts systemic regulation through multiple organ axes, including adipose tissue (adipokines and inflammation), gut microbiota, liver (SIRT1/FGF21 signaling), and the brain (hypothalamic-pituitary-adrenal axis and myokines such as BDNF and CTSB for bidirectional neuroimmune regulation). In summary, exercise directly remodels the local immune crosstalk network in skeletal muscle and synergistically improves T2DM-associated muscle atrophy through multi-organ interactions, providing a theoretical basis for precise exercise interventions.</p>

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Exercise remodels the skeletal muscle immune microenvironment to ameliorate type 2 diabetes mellitus-induced muscle atrophy: From immunometabolism to organ crosstalk

  • 期刊论文

  • 发表日期：

    2026年7月4日

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  • Fu Pengyu,
  • Xu Huiyun,
  • Gong Lijing

摘要

Type 2 diabetes mellitus (T2DM) complicated by muscle atrophy (diabetic sarcopenia) significantly increases mortality risk, with immunometabolic imbalance-driven disruption of the skeletal muscle microenvironment as a core mechanism. This review focuses on the immune cell–myocyte crosstalk network to elucidate the pathological mechanisms of T2DM-induced muscle atrophy, the local remodeling effects of exercise, and systemic organ crosstalk. In the T2DM state, M1/M2 imbalance and metabolic reprogramming of macrophages, dysregulated mast cell activation and histamine signaling, NLRP3 inflammasome-mediated pyroptosis, T-cell immunosenescence, and chemokine storms collectively disrupt muscle homeostasis. Exercise reverses these abnormalities by downregulating TRIB3/AKT to promote M2 polarization, restoring mast cell function, inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway, increasing Treg infiltration, and downregulating the chemokine network, thereby shifting the local microenvironment from a “pro-inflammatory/destructive” to a “reparative/regenerative” state. Furthermore, exercise exerts systemic regulation through multiple organ axes, including adipose tissue (adipokines and inflammation), gut microbiota, liver (SIRT1/FGF21 signaling), and the brain (hypothalamic-pituitary-adrenal axis and myokines such as BDNF and CTSB for bidirectional neuroimmune regulation). In summary, exercise directly remodels the local immune crosstalk network in skeletal muscle and synergistically improves T2DM-associated muscle atrophy through multi-organ interactions, providing a theoretical basis for precise exercise interventions.