This review systematically summarizes the molecular mechanisms by which exercise suppresses excessive neuronal apoptosis in PD

The gap

Evidence profile

Sourced from the future work of the source papers, classified as general, drawn from work published between 2025 and 2026, spanning 4 journals. Those papers have been cited 1 times in total.

Supporting evidence — 4 representative gaps

• Shared mechanisms of musculoskeletal dysfunction in type 2 diabetes mellitus: Insights into future therapeutic directions (Review) (2026) · International Journal of Molecular Medicine · doi

  1. Introduction According to the International Diabetes Federation (IDF), an estimated 537 million adults aged 20‑79 years worldwide had diabetes in 2021. Projections indicate this number will rise to 783 million by 2045 (1). Notably, over 90% of these cases are type 2 diabetes mellitus (T2DM) (2). Inadequately managed T2DM can lead to numerous severe complications. Within the musculoskeletal system, T2DM induces multiple pathological alterations affecting bone, joints, muscles and the nervous system. These impairments not only directly compromise mobility but are also intrinsically linked to metabolic dysregu‑ lation, chronic inflammation and microvascular dysfunction. Physical exercise is an important intervention for diabetes management. Exercise activates adenosine monophos‑ phate‑activated protein kinase (AMPK) signaling, promotes glucose transport and lipid metabolism, and enhances mito‑ chondrial function in skeletal muscle. It also improves insulin sensitivity and blood sugar control (3‑8). However, a scientific exercise plan fundamentally relies on a stable and functional musculoskeletal system. Because of the detrimental impact of T2DM on the musculoskeletal system, early intervention is critical. Identifying effective treatment targets and preventive strategies may reduce the need for surgery and significantly 2 HE et al: SYSTEMIC MUSCULOSKELETAL DYSFUNCTION IN T2DM improve the quality of life for patients. This approach aligns with current priorities in the prevention and management of major diseases, emphasizing the integration of traditional Chinese and Western medicine, as well as multidisciplinary collaboration. The present review synthesizes current research to explain how T2DM affects the musculoskeletal system and identifies potential intervention targets, thereby laying a solid foundation for future investigations. 2. Systemic pathophysiology of T2DM in musculoskeletal tissues Hyperglycemia and insulin resistance as the primary instigators. Hyperglycemia and insulin resistance represent the earliest pathological events that start musculoskeletal degeneration in T2DM. Persistent metabolic dysregulation disrupts glucose utilization, energy metabolism and cellular anabolic signaling. This creates a common pathological basis for abnormalities in skeletal muscle, tendon, tendon‑bone interface (TBI) and bone. Although these tissues perform distinct physiological functions, they all exhibit impaired cellular metabolism and tissue homeostasis under chronic hyperglycemic and insulin‑resistant conditions (Table I). Skeletal muscle is the primary site for post‑prandial glucose uptake and disposal, playing a central role in maintaining glucose homeostasis (9). Peripheral insulin resistance origi‑ nating in skeletal muscle is a key driver in the development and progression of T2DM (10). Under normal physiological condi‑ tions, insulin prom

  generalfuture work
  Keywords: musculoskeletal insulin system diabetes glucose skeletal muscle pathological bone exercise intervention metabolism resistance million metabolic
• Pyroptosis and HMGB1 Signaling in T2DM-Related Sarcopenia: Current Evidence, Mechanistic Framework, and Exercise Implications (2026) · Health and Metabolism · doi

  In summary, accumulating evidence suggests that metabolic inflammation, inflammasome activation, and HMGB1 signaling may collectively contribute to the complex pathophysiology of T2DM-related sarcopenia. The available literature indicates that hyperglycemia, lipotoxicity, and oxidative stress can create a metabolic environment that is permissive for inflammatory signaling pathways, including those associated with the NLRP3 inflammasome and pyroptosis. Under such conditions, the release of inflammatory mediators and damage- associated molecular patterns such as HMGB1 may further influence immune–metabolic interactions and cellular homeostasis. However, most mechanistic insights supporting these interactions are derived from experimental systems or non-muscle tissues, and direct evidence demonstrating coordinated activation of pyroptosis and HMGB1 signaling in skeletal muscle from patients with confirmed T2DM-related sarcopenia remains limited. Within this conceptual framework, exercise represents a promising non-pharmacological strategy for improving metabolic and inflammatory disturbances associated with T2DM-related muscle dysfunction. Exercise training can influence several upstream metabolic regulators, including mitochondrial function, oxidative stress balance, and inflammatory signaling pathways. Activation of metabolic regulators such as the AMPK-PGC-1α axis, together with improvements in mitochondrial quality control and autophagic processes, may contribute to the overall anti-inflammatory and metabolic benefits of exercise. Nevertheless, these mechanisms should currently be interpreted as indirect regulatory pathways rather than direct evidence that exercise specifically inhibits a pyroptosis-HMGB1 signaling axis in skeletal muscle. Future research should focus on clarifying the role of inflammatory cell-death pathways in diabetic skeletal muscle through integrated human and experimental studies. In particular, priority should be given to: (1) determining whether exercise interventions modulate intramuscular markers of pyroptosis and HMGB1 signaling in individuals with confirmed T2DM-related sarcopenia; and (2) defining the dose-response relationships and molecular mechanisms by which different exercise modalities influence immunometabolic regulation in skeletal muscle. Such studies will be essential for translating mechanistic insights into evidence-based exercise prescriptions for the prevention and management of T2DM-related sarcopenia. Author Contributions: Y.S.: was responsible for drafting and revising the manuscript; P.F.: contributed to the overall manuscript structure and revisions; S.L.: provided revisions and constructive suggestions; L.G.: determined the research topic and provided revisions and constructive suggestions. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by the National Natural Science Foundation of China (32501019). Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Data Availability Statement: Not applicable. Conflicts of Interest: The authors declare no conflict of interest. 10 of 15 Health Metab. 2026, 3(3), 5 https://doi.org/10.53941/hm.2026.100019 Use of AI and AI-Assisted Technologies: During the preparation of this work, the authors used OpenAI to assist with language polishing and editing. After using this tool, the authors reviewed and edited the content as needed and take full responsibility for the content of the published article.

  generalfuture work
  Keywords: metabolic exercise signaling inflammatory muscle hmgb related evidence sarcopenia pathways pyroptosis skeletal authors activation associated
• Kinase–phosphatase balance in exercise adaptation: phosphorylation programs, PTM crosstalk, and actionable gaps (2025) · Frontiers in Sports and Active Living · doi

  important is not merely a simple on-off switch; rather, Phosphorylation, regulated by kinases and phosphatases, is a key molecular axis implicated in exercise-induced adaptations. It controls like mitochondrial cellular processes biogenesis, muscle hypertrophy, and metabolic flexibility. This balance it constitutes a complex regulatory hub that uses mechanical, metabolic, and hormonal signals to make sure that molecular responses match the needs of exercise. HIIT may induce an increase in PHLPP2 expression, which has been proposed to help restrain excessive Akt activation and prevent maladaptation, whereas during endurance training, PHLPP activity tends to remain low, supporting Akt-dependent mitochondrial biogenesis. We currently lack essential knowledge about the functional interaction between phosphorylation dynamics and epigenetic regulation. Exercise is accompanied by histone acetylation, such as heightened acetylation at mitochondrial-gene promoters during endurance exercise, and can also trigger DNA methylation at linked to fiber type during resistance training. However, the mechanisms by which the kinase– phosphatase network facilitates these epigenetic modifications are not yet fully understood. One important question is whether AMPK, the main energy-sensing kinase, connects energetic stress to chromatin remodeling by adding phosphate groups to or histone-modifying deacetylases, and another key question is whether the regulation of Akt activity of methyltransferases like EZH2. These enzymes are responsible for signaling by PHLPP acetyltransferases enzymes alters loci like the and

  generalfuture work
  Keywords: exercise like mitochondrial phlpp important phosphorylation molecular biogenesis metabolic endurance training activity epigenetic regulation histone
• Exercise suppresses apoptosis for alleviating Parkinson’s disease: effects on pathophysiological molecular pathways (2026) · Frontiers in Aging Neuroscience · cited 1× · doi

  This review systematically summarizes the molecular mecha- nisms by which exercise suppresses excessive neuronal apoptosis in PD through regulating mitochondrial function (AMPK/Sirt1/ PGC-1α), neuroinflammation (TLR/MyD88/NF-κB), and autoph- agy (CaMKII/Beclin1/p62). These pathways do not operate in isolation but form an integrated network, with AMPK serving as a central hub coordinating mitochondrial biogenesis, autophagic flux, and anti-inflammatory responses. Given the ameliorative effects of exercise on PD pathology and symptoms, coupled with

  generalfuture work
  Keywords: exercise mitochondrial ampk review systematically summarizes molecular mecha nisms suppresses excessive neuronal apoptosis regulating function

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