Type 2 diabetes mellitus (T2DM) is a common metabolic disease that is frequently accompanied by multiple complications, including diabetic myopathy, a muscle disorder that is mainly manifested as decreased muscle function and reduced muscle mass. Diabetic myopathy is a relatively common complication among patients with diabetes that is mainly attributed to mitochondrial dysfunction. Therefore, we investigated the mechanisms underlying diabetic myopathy development, focusing on the role of microRNAs (miRs). Zebrafish were fed a high-sugar diet for 8 weeks and immersed in a glucose solution to establish a model of T2DM. Notably, the fish exhibited impaired blood glucose homeostasis, increased lipid accumulation in the skeletal muscles, and decreased insulin levels in the skeletal muscle. Additionally, we observed various symptoms of diabetic myopathy, including a decreased cross-sectional area of skeletal muscle fibers, increased skeletal muscle fibrosis, a significant decline in exercise capacity, and a significant decrease in mitochondrial respiratory function. Mechanistically, bioinformatic analysis combined with various molecular analyses showed that the miR-139-5p/NAMPT pathway was involved in long-term high-glucose-induced mitochondrial dysfunction in the skeletal muscle, leading to diabetic myopathy. Conclusively, this study provides a basis for the development of novel strategies for the prevention and treatment of diabetic myopathy.

Background: Diabetic cardiomyopathy (DCM) is characterized by progressive cardiac dysfunction, metabolic dysregulation, myocardial fibrosis, and mitochondrial impairment. Existing animal models, such as streptozotocin (STZ)-induced models, suffer from high mortality and fail to replicate chronic metabolic dysregulation induced by high-fat diets (HFD), whereas HFD or HFD/STZ-combined rodent models require high maintenance costs. This study aimed to establish a zebrafish HFD-DCM model to facilitate mechanistic exploration and drug discovery. Methods: Eighty wild-type female zebrafish were divided into normal diet (N, 6% fat) and HFD (H, 24% fat) groups and fed the diet for 8 weeks. Metabolic phenotypes were evaluated using intraperitoneal glucose tolerance tests and insulin level analysis. Cardiac function was assessed by using echocardiography (ejection fraction, E peak). Structural, metabolic, and oxidative stress alterations were analyzed by histopathology (H&E, Masson, and Oil Red O staining), molecular assays (RT-qPCR, Western blotting), and mitochondrial structure/function evaluations (respiratory chain activity, transmission electron microscopy, and DHE staining). Results: HFD-fed zebrafish developed obesity, insulin resistance, and impaired glucose tolerance. Echocardiography revealed cardiac hypertrophy, reduced ejection fraction, and diastolic dysfunction. Excessive lipid accumulation, upregulated fibrosis/inflammatory markers, impaired mitochondrial respiration, elevated reactive oxygen species levels, and a disrupted redox balance were observed. Conclusions: We established a female zebrafish HFD model that recapitulates human DCM features, including hypertrophy, metabolic dysregulation, fibrosis, inflammation, and mitochondrial dysfunction. This model offers novel insights into DCM pathogenesis and serves as a valuable platform for mechanistic studies and targeted drug screening.

Type 2 diabetes mellitus (T2DM) is characterized by skeletal muscle insulin resistance, which contributes to systemic metabolic dysregulation and diabetic myopathy (DM), a complication involving the loss of muscle mass and contractile function. Although hypoxic exercise has demonstrated metabolic benefits in chronic diseases, its efficacy against DM remains unclear. We hypothesized that hypoxic exercise would be more effective than normoxic exercise in ameliorating diabetic myopathy-associated skeletal muscle abnormalities. Accordingly, adult zebrafish underwent an 8-week high-glucose intervention combining high-glucose feeding and glucose immersion to establish a T2DM-associated diabetic myopathy model and were subsequently subjected to 5 weeks of normoxic or hypoxic exercise (28.8 cm/s, corresponding to 70% of critical swimming speed (Ucrit) determined under normoxic conditions, 2 h/day, 5 days/week) to compare their effects on skeletal muscle outcomes. Hypoxic exercise produced greater improvements in glucose tolerance and locomotor performance than normoxic exercise, while the effects on skeletal muscle morphological and atrophy-related indices varied across outcomes. Both normoxic exercise and intermittent hypoxic exposure altered the abundance of mitochondrial quality-control-related proteins in the skeletal muscle of zebrafish with diabetic myopathy, whereas hypoxic exercise produced more pronounced changes in several of these proteins. Moreover, hypoxic exercise more markedly increased the abundance of mitochondrial respiratory-chain proteins than aerobic exercise or intermittent hypoxic exposure alone. Marked reactive oxygen species (ROS) accumulation was observed in the skeletal muscle of zebrafish with diabetic myopathy. Both aerobic and hypoxic exercise effectively reduced excessive ROS production, with hypoxic exercise producing the greater effect. Analysis of Foxo3a and its phosphorylation showed that p-Foxo3a expression decreased most prominently in the T2DM hypoxia exercise (DHE) group, indicating that hypoxic exercise is associated with modulation of Hif1a/Foxo3a-related signaling. Hypoxic exercise was associated with greater Hif1a protein abundance and lower Foxo3a Ser253 phosphorylation than normoxic exercise, accompanied by improved mitochondrial quality control and reduced ROS accumulation. In conclusion, hypoxic exercise ameliorated diabetic skeletal myopathy and was accompanied by modulation of Hif1a/Foxo3a-related signaling, more favorable mitochondrial morphology, altered abundance of mitochondrial quality-control-related and respiratory-chain proteins, and reduced dihydroethidium-detectable oxidative signals.

Post-stroke cognitive impairment (PSCI) is a frequent and disabling consequence of stroke that limits long-term recovery and quality of life. Disruption of the hippocampal neurogenic niche may impair adult hippocampal neurogenesis (AHN), while exercise is increasingly recognized as a promising non-pharmacological strategy for cognitive rehabilitation. This review synthesizes evidence that exercise may shift the post-stroke hippocampal niche from a hostile to a permissive state through coordinated regulation of neuroinflammation, neurovascular integrity, and mitochondrial homeostasis. We distinguish increased progenitor proliferation from productive neurogenesis, defined by the survival, maturation, appropriate positioning, and functional integration of newborn neurons. Exercise may attenuate inflammatory signaling, support angiogenesis and blood–brain barrier repair, and improve mitochondrial biogenesis and quality control; however, much of the mechanistic evidence remains preclinical, and increases in early neurogenic markers do not by themselves establish functional neuronal integration or causality. Current clinical evidence supports cognitive benefits of exercise more strongly than it supports AHN as the indispensable mediator of those benefits. A productive-neurogenesis framework therefore provides a more rigorous basis for interpreting existing studies and designing future experiments that combine lineage tracing, temporally controlled neurogenesis ablation, circuit-level analysis, and domain-specific cognitive outcomes.