Boldine attenuates diabetes-induced skeletal muscle dysfunction

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 dysfuntion and explored underlying mechanisms. Diabetes was induced in male C57BL/6 J 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 Ca 2 ⁺, nitric oxide, inflammasome-related gene levels, and PPARγ reactivity. 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 were reduced by ~ 50% with treatment. In vitro, high glucose increased ethidium uptake, Ca 2 ⁺, nitric oxide production, inflammasome-related gene levels, and nuclear PPARγ localization; all were attenuated by boldine. Boldine preserves skeletal muscle function, vascular reactivity, and metabolic homeostasis in diabetes, preventing lipid accumulation and upregulation of inflammasome components mRNA levels. These effects involve inhibition of large-pore channels, reducing membrane permeability and Ca 2 ⁺-dependent inflammatory signaling, highlighting their therapeutic potential as targets for diabetes-induced muscle dysfunction. In myoblasts, high glucose increases large-pore channel activity, elevating cytoplasmic Ca 2 ⁺ concentration and nitric oxide generation, which contribute to increasing the activity of large-pore channels (including Cx-formed hemichannels and P2X7Rs), raising the levels of inflammasome components, and promoting lipid accumulation. In STZ-diabetic mice, de novo expression of large-pore channels in skeletal muscles contributes to reducing the resting membrane potential of myofibers, as well as reducing the blood perfusion of muscles, muscle weakness, PPARɤ activation and the accumulation of intramuscular fat. Boldine inhibits large-pore channel activity and, consequently, prevents the above alterations, preserving skeletal muscle function in vivo .