Mitochondrial cristae density is increased following high-intensity interval training in patients with type 2 diabetes

Aims/hypothesis: Mitochondrial cristae architecture is a key determinant of oxidative capacity in skeletal muscle. While mitochondrial dysfunction is common in type 2 diabetes, it remains unclear whether cristae density is reduced and whether it can be improved by exercise training. We therefore investigated the mitochondrial cristae density in skeletal muscle of patients with type 2 diabetes compared with glucose-tolerant obese and lean individuals, and examined the effect of high-intensity interval training (HIIT). Methods: In a non-randomized intervention study, male participants (aged 40-65 years) with type 2 diabetes (n=15), weight-matched obese controls (n=15), and lean controls (n=18) completed an 8-week supervised HIIT intervention combining rowing and cycling. Muscle biopsies from the m. vastus lateralis were analyzed using transmission electron microscopy (TEM) to quantify mitochondrial cristae density (cristae surface area per mitochondrial volume) and to derive cristae surface area per muscle volume, integrating mitochondrial abundance and ultrastructure. To ensure high stereological precision, a minimum of 49 mitochondrial profiles per sample were analyzed. Results: No differences in mitochondrial cristae density were observed between groups at baseline. HIIT induced an ~7% increase in cristae density across all groups, with the most pronounced adaptations in type 2 fibers and in the intermyofibrillar compartment. At baseline, patients with type 2 diabetes exhibited lower cristae surface area per muscle volume compared with lean controls. Notably, cristae surface area per muscle volume increased more than mitochondrial volume density alone, reflecting combined structural and volumetric remodeling. Conclusions/interpretation: Skeletal muscle mitochondrial cristae density is not different between patients with type 2 diabetes and glucose-tolerant obese and lean controls, and the capacity for cristae remodeling in response to exercise is not affected by type 2 diabetes. These findings highlight the plasticity of mitochondrial architecture and support HIIT as a potent stimulus for improving muscle oxidative and metabolic health, also in type 2 diabetes.