Higher mitochondrial respiration and uncoupling with reduced electron transport chain content in vivo in muscle of sedentary versus active subjects

Abstract

Objective: This study investigated the disparity between muscle metabolic rate and mitochondrial metabolism in human muscle of sedentary vs. active individuals.

Research design and methods: Chronic activity level was characterized by a physical activity questionnaire and a triaxial accelerometer as well as a maximal oxygen uptake test. The ATP and O(2) fluxes and mitochondrial coupling (ATP/O(2) or P/O) in resting muscle as well as mitochondrial capacity (ATP(max)) were determined in vivo in human vastus lateralis muscle using magnetic resonance and optical spectroscopy on 24 sedentary and seven active subjects. Muscle biopsies were analyzed for electron transport chain content (using complex III as a representative marker) and mitochondrial proteins associated with antioxidant protection.

Results: Sedentary muscle had lower electron transport chain complex content (65% of the active group) in proportion to the reduction in ATP(max) (0.69 ± 0.07 vs. 1.07 ± 0.06 mM sec(-1)) as compared with active subjects. This lower ATP(max) paired with an unchanged O(2) flux in resting muscle between groups resulted in a doubling of O(2) flux per ATP(max) (3.3 ± 0.3 vs. 1.7 ± 0.2 μM O(2) per mM ATP) that reflected mitochondrial uncoupling (P/O = 1.41 ± 0.1 vs. 2.1 ± 0.3) and greater UCP3/complex III (6.0 ± 0.7 vs. 3.8 ± 0.3) in sedentary vs. active subjects.

Conclusion: A smaller mitochondrial pool serving the same O(2) flux resulted in elevated mitochondrial respiration in sedentary muscle. In addition, uncoupling contributed to this higher mitochondrial respiration. This finding resolves the paradox of stable muscle metabolism but greater mitochondrial respiration in muscle of inactive vs. active subjects.

Figures

Fig. 1.

ATP flux (A), O2 flux (B), and mitochondrial coupling (C) in individuals from the active (■) and sedentary (▵) groups. The horizontal dashed line in panel C represents the theoretical value for mitochondrial coupling with glucose as substrate (28). *, P < 0.05. Sample sizes for active and sedentary groups, respectively, are: n = 7 and 21 (A); n = 6 and 17 (B); and n = 6 and 17 (C).

Fig. 2.

Muscle energy fluxes normalized to mitochondrial content or capacity in vastus lateralis of active (■) and sedentary (▵) subjects: ATPmax/CIII (A), ATP flux/ATPmax (B), and O2 flux/ATPmax (C). *, P < 0.03; **, P < 0.004. Sample sizes for active and sedentary groups, respectively, are: n = 6 and 14 (A); n = 7 and 21 (B); and n = 6 and 17 (C).

Fig. 3.

UCP3 protein content per cell (A) and per CIII of the electron transport chain (B) in vastus lateralis of active (■) and sedentary (▵) subjects. *, P < 0.05. Relationship between mitochondrial coupling and total UCP3 (C) or UCP3 per CIII of the electron transport chain (D) indicates increased uncoupling protein level with mitochondrial uncoupling among the subjects of the study.

Fig. 4.

SOD2 protein content per cell (A) and per CIII of the electron transport chain (B) in vastus lateralis of active (■) and sedentary (▵) subjects. ***, P < 0.001. Relationship between mitochondrial coupling and total SOD2 (C) or SOD2 per CIII (D) among the subjects of the study is shown.