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

Aims/hypothesisMitochondrial 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 individuals with obesity and lean individuals, and examined the effect of high-intensity interval training (HIIT). MethodsIn a non-randomized intervention study, the effect of an 8-week supervised HIIT intervention combining rowing and cycling was examined in male participants (aged 40-65 years) with type 2 diabetes (n=15), glucose-tolerant individuals with obesity (n=15), and lean individuals (n=18). 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. ResultsNo 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 individuals. Notably, cristae surface area per muscle volume increased more than mitochondrial volume density alone, reflecting combined structural and volumetric remodeling. Conclusions/interpretationSkeletal muscle mitochondrial cristae density is not different between patients with type 2 diabetes and glucose-tolerant individuals with obesity and lean individuals, 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. Research in Context What is already known about this subject?O_LISkeletal muscle mitochondrial cristae architecture is critical for oxidative phosphorylation and metabolic health. C_LIO_LIType 2 diabetes is associated with altered mitochondrial structure, but whether cristae density is reduced remains unclear. C_LIO_LIPrevious short-term exercise interventions have shown limited or inconsistent effects on mitochondrial cristae density, possibly due to methodological constraints. C_LI What is the key question?O_LICan high-intensity interval training (HIIT) remodel skeletal muscle mitochondrial cristae in patients with type 2 diabetes, and is baseline cristae density altered in this condition? C_LI What are the new findings?O_LIBaseline mitochondrial cristae density does not differ between patients with type 2 diabetes and glucose-tolerant individuals with obesity and lean individuals, but cristae surface area per muscle volume is lower in type 2 diabetes. C_LIO_LIEight weeks of HIIT increased mitochondrial cristae density by [~]7% across all groups, with cristae surface area per muscle volume increasing more than mitochondrial volume density alone. C_LIO_LIExercise-induced cristae remodeling occurs in both muscle fiber types and subcellular compartments, demonstrating preserved structural plasticity in type 2 diabetes. C_LI How might this impact on clinical practice in the foreseeable future?O_LIHIIT represents a potent intervention to improve mitochondrial architecture and potentially enhance muscle oxidative capacity and metabolic health in individuals with type 2 diabetes. C_LI