Boldine attenuates diabetes-induced skeletal muscle dysfunction

Abstract Background Diabetes mellitus is associated with skeletal muscle dysfunction, including reduced strength, impaired perfusion, lipid accumulation, and inflammation. Activation of large-pore channels increases membrane permeability and inflammatory signaling. Boldine, an alkaloid from Peumus boldus , inhibits these channels and exhibits antioxidant and anti-inflammatory properties. This study evaluated whether boldine prevents diabetes-induced skeletal muscle alterations and explored underlying mechanisms. Methods Diabetes was induced in male C57BL/6J mice using streptozotocin (40 mg/kg/day for 5 days), followed by boldine treatment (50 mg/kg/day, 4 weeks). Muscle strength, resting membrane potential, and gastrocnemius perfusion were assessed. Lipid accumulation, capillary density, and NLRP3 mRNA were analyzed. Human myoblasts (AB1167) under low or high glucose with or without boldine were evaluated for membrane permeability, intracellular Ca²⁺, nitric oxide, inflammasome-related gene expression, and PPARγ reactivity. Results Diabetic mice exhibited reduced muscle strength, membrane depolarization, and ~ 20% lower basal perfusion, all prevented by boldine. Lipid accumulation increased to 52.4 ± 3.6% in diabetic muscle and decreased to 15.2 ± 4.1% with boldine (control: 3.1 ± 1.3%; p < 0.05). NLRP3 mRNA levels increased 17.7-fold and was reduced by ~ 50% with treatment. In vitro, high glucose increased ethidium uptake, Ca²⁺, nitric oxide production, inflammasome-related gene levels, and nuclear PPARγ localization; all were attenuated by boldine. Conclusions Boldine preserves skeletal muscle function, vascular reactivity, and metabolic homeostasis in diabetes, preventing lipid accumulation and inflammasome activation. These effects involve inhibition of large-pore channels, reducing membrane permeability and Ca²⁺-dependent inflammatory signaling, highlighting their role as therapeutic targets in diabetes-induced muscle dysfunction.