Nine months of combined training improves ex vivo skeletal muscle metabolism in individuals with type 2 diabetes

Abstract

Context: Type 2 diabetes (T2D) has features of disordered lipid and glucose metabolism, due in part to reduced mitochondrial content.

Objective: Our objective was to investigate effects of different types of exercise on mitochondrial content and substrate oxidation in individuals with T2D (ancillary study of the randomized controlled trial Health Benefits of Aerobic and Resistance Training in Individuals with Type 2 Diabetes, HART-D).

Intervention: T2D individuals were randomized to aerobic training (AT, n = 12), resistance training (RT, n = 18), combination training (ATRT, n = 12), or nonexercise control (n = 10). Blood draws, peak oxygen consumption tests, dual-energy x-ray absorptiometry scans and muscle biopsies of vastus lateralis were performed before and after 9 months. Ex vivo substrate oxidations ((14)CO2), mitochondrial content, and enzyme activities were measured. Glycated hemoglobin A1c and free fatty acids were also determined.

Results: Mitochondrial content increased after RT and ATRT. Octanoate oxidation increased after AT and ATRT, whereas palmitate, pyruvate, and acetate oxidations increased in all exercise groups. Exercise-induced responses in mitochondrial DNA were associated with improvements in peak oxygen consumption, β-hydroxyacyl-coenzyme A dehydrogenase activity, and palmitate oxidation.

Conclusions: Nine months of AT and RT significantly improved most aspects of skeletal muscle mitochondrial content and substrate oxidation, whereas the combination improved all aspects. These exercise responses were associated with clinical improvements, indicating that long-term training, especially combination, is an effective lifestyle therapy for individuals with T2D by way of improving muscle substrate metabolism.

Figures

Figure 1.

Skeletal muscle mitochondrial content. Fifty-two individuals with T2D were randomized to 1 of 4 groups for a 9-month intervention and underwent skeletal muscle biopsies at baseline and 9 months: nonexercise control (n = 10), AT (n = 12), RT (n = 18), and ATRT (n = 12). A and B, Mitochondrial content was assessed by mtDNA copy number via quantitative PCR (A) and protein content of electron transport system complexes (OXPHOS) via Western immunoblotting (B). C and D, BHAD (C), a key enzyme in fatty acid oxidation, and CS (D), a critical enzyme in the TCA cycle, were measured in skeletal muscle homogenates. Data are presented as mean ± SEM. The mtDNA copy number was not normally distributed. *P < .05; **P < .01 vs control; $P < .05 vs AT.

Figure 2.

Skeletal muscle fatty acid oxidation. Fifty-two individuals with T2D were randomized to 1 of 4 groups for a 9-month intervention and underwent skeletal muscle biopsies at baseline and 9 months: nonexercise control (n = 10), AT (n = 12), RT (n = 18), and ATRT (n = 12). A and B, Long-chain fatty acid oxidation to CO2 was assessed using [1-14C]palmitate for complete oxidation (A) and the ratio of complete to incomplete oxidation (B). C, Medium-chain fatty acid oxidation to CO2 was measured using [1-14C]octanoate. Data are presented as mean ± SEM. All substrate oxidation data were not normally distributed. *P < .05; **P < .01 vs control; $P < .05 vs RT.

Figure 3.

Skeletal muscle TCA cycle flux. Fifty-two individuals with T2D were randomized to 1 of 4 groups for a 9-month intervention and underwent skeletal muscle biopsies at baseline and 9 months: nonexercise control (n = 10), AT (n = 12), RT (n = 18), and ATRT (n = 12). A and B, To investigate the flux through the TCA cycle, oxidation to CO2 was assessed using [1-14C]pyruvate (A) and [1-14C]acetate (B). Data are presented as mean ± SEM. All substrate oxidation data were not normally distributed. *P < .05; **P < .01 vs control.

Figure 4.

Changes in mitochondrial content related to changes in clinical and functional outcomes. Fifty-two individuals with T2D were randomized to 1 of 4 groups for a 9-month intervention and underwent skeletal muscle biopsies at baseline and 9 months. We collapsed the exercise groups and performed Spearman correlation analyses: AT (n = 12), RT (n = 18), and ATRT (n = 12). A–D, We present the relationships between the changes in mtDNA copy number and the changes in VO2peak (A), HbA1c (B), BHAD activity (C), and palmitate oxidation to CO2 (D). The mtDNA copy number and palmitate oxidation data were not normally distributed.