Songbo Li

The pathological mechanisms of type 2 diabetes mellitus (T2DM)-related sarcopenia are complex. Classical explanations based on insulin resistance, mitochondrial dysfunction and impaired protein turnover do not fully explain the chronic inflammatory microenvironment observed in diabetic skeletal muscle. Inflammatory cell death and damage-associated molecular pattern responses have attracted increasing attention in metabolic disease research. Evidence from diabetic muscle models, insulin resistance models and other diabetic complications suggests that pyroptosis-related signaling and high mobility group box 1 (HMGB1)-associated inflammatory responses may participate in the metabolic-inflammatory environment associated with T2DM-related sarcopenia. Direct evidence from human skeletal muscle remains limited, and the relationship between these processes has not been clearly defined in this condition. This narrative review summarizes current evidence for inflammasome- and gasdermin-related pyroptotic signaling, HMGB1-associated damage signaling and their potential relevance to diabetic skeletal muscle. It also discusses exercise as a modulator of upstream metabolic and inflammatory stress, including mitochondrial dysfunction, oxidative stress, autophagic flux and selected inflammasome-related markers. Finally, given the current lack of direct skeletal muscle evidence, future research directions are proposed to inform future mechanistic studies and the rational design of exercise interventions for T2DM-related sarcopenia.

Physical inactivity contributes to type 2 diabetes (T2D), but the molecular links between exercise and metabolic improvement remain incompletely understood. We meta-analyzed genome-wide association studies of vigorous physical activity and T2D (combined n ≈ 1.95 million) and integrated eQTL/sQTL maps with single-cell and spatial transcriptomic datasets to connect genetic risk with tissues, cell types, and regulatory programs. Tissue and cell-type enrichment, colocalization, and network analyses were performed. Computational findings were further examined in male 10-week-old C57BL/6J mice with high-fat diet-induced diabetes. After 1 week of acclimatization, mice were randomly assigned to normal chow, high-fat diet, or high-fat diet plus exercise groups (n = 6 per group; high-fat diet with 60% of total energy from fat). The exercise intervention consisted of treadmill running (10 m/min for 50 min per day, 5 days per week, total 16 weeks), followed by metabolic phenotyping, skeletal muscle histology, bulk RNA sequencing, alternative splicing analysis, and RT-qPCR of Mau2 isoforms. Exercise- and T2D-associated variants showed joint enrichment in skeletal muscle and adipose eQTL/sQTL signals. Integrated single-cell analyses prioritized fibro-adipogenic progenitors and endothelial cells, and identified an extracellular matrix- and collagen-related module in fibro-adipogenic progenitors associated with both exercise and T2D. Mau2 emerged as a shared candidate gene with tissue-specific splicing signals. In diabetic mice, exercise improved glucose homeostasis and muscle fiber structure, and reduced Mau2 intron retention in skeletal muscle without changing total Mau2 expression. These findings support a multiscale framework linking exercise-responsive regulation to T2D-related tissue remodeling and splicing plasticity.