E-cigarette exposure impairs skeletal muscle mitochondrial function in male mice.

While conventional tobacco-cigarette smoking continues to decline, e-cigarette (E-cig) use is rising, yet its physiological consequences remain poorly characterized. Chronic activation of the aryl hydrocarbon receptor (AHR) by tobacco smoke impairs skeletal muscle mitochondrial function. Here, we evaluated whether E-cig vapor elicits AHR activation and mitochondrial dysfunction in skeletal muscle. C2C12 mouse myoblasts were exposed to 1% dimethyl sulfoxide (vehicle), 0.02% tobacco-smoke condensate (TSC), or vape condensate (VC) at 0.006%, 0.06%, and 0.3%. Cell viability, AHR-pathway gene expression (Ahr, Ahrr, Cyp1a1), and mitochondrial respiration were assessed. Male C57BL/6J mice (12-16 weeks; n = 4-5/group) underwent acute 2-h or 4-week exposure to room air, tobacco smoke, or E-cig vapor. Serum cotinine, gastrocnemius AHR-pathway genes, muscle contractility, and mitochondrial function were evaluated. In myoblasts, 0.02% TSC and 0.3% VC upregulated Ahrr and Cyp1a1 (p < 0.0001) and reduced complex I state-3 respiration (p < 0.05) without affecting viability. In mice, acute exposure to tobacco smoke and E-cig vapor significantly increased serum cotinine (p < 0.0001), but only tobacco-smoke activated AHR-pathway. Chronic exposure to tobacco smoke and E-cig vapor reduced mitochondrial complex I and II state-3 respiration (p < 0.05), without altering muscle contractile function. These findings suggest that AHR-independent mechanisms contribute to mitochondrial dysfunction with E-cig vapor exposure.