Exercise training improves vascular mitochondrial function

Abstract

Exercise training is recognized to improve cardiac and skeletal muscle mitochondrial respiratory capacity; however, the impact of chronic exercise on vascular mitochondrial respiratory function is unknown. We hypothesized that exercise training concomitantly increases both vascular mitochondrial respiratory capacity and vascular function. Arteries from both sedentary (SED) and swim-trained (EX, 5 wk) mice were compared in terms of mitochondrial respiratory function, mitochondrial content, markers of mitochondrial biogenesis, redox balance, nitric oxide (NO) signaling, and vessel function. Mitochondrial complex I and complex I + II state 3 respiration and the respiratory control ratio (complex I + II state 3 respiration/complex I state 2 respiration) were greater in vessels from EX relative to SED mice, despite similar levels of arterial citrate synthase activity and mitochondrial DNA content. Furthermore, compared with the SED mice, arteries from EX mice displayed elevated transcript levels of peroxisome proliferative activated receptor-γ coactivator-1α and the downstream targets cytochrome c oxidase subunit IV isoform 1,isocitrate dehydrogenase(Idh)2, and Idh3a, increased manganese superoxide dismutase protein expression, increased endothelial NO synthase phosphorylation (Ser(1177)), and suppressed reactive oxygen species generation (all P< 0.05). Although there were no differences in EX and SED mice concerning endothelium-dependent and endothelium-independent vasorelaxation, phenylephrine-induced vasocontraction was blunted in vessels from EX compared with SED mice, and this effect was normalized by NOS inhibition. These training-induced increases in vascular mitochondrial respiratory capacity and evidence of improved redox balance, which may, at least in part, be attributable to elevated NO bioavailability, have the potential to protect against age- and disease-related challenges to arterial function.

Keywords: arterial function; mitochondria; redox balance; vasculature.

Fig. 1.

Vascular mitochondrial respiratory capacity increases in response to exercise training. A: citrate synthase activity (CSA) in gastrocnemius muscle (n = 6). B: mitochondrial oxygen consumption in permeabilized aortas from exercise-trained (EX) and sedentary (SED) mice normalized to vessel wet weight. C I State 2, complex I state 2 respiration; C I State 3, complex I state 3 (following ADP stimulation); and C I + II State 3, complex I and II state 3 respiration (following ADP stimulation). C: respiratory control ratio (RCR), complex I + II state 3 normalized to complex I state 2 (n = 8 animals, 16 vessels). D and E: mRNA expression of Ppargc1a (D) and genes involved in mitochondrial bioenergetics (E) following EX (n = 8). Data are presented as a fold change relative to SED, n = 8. F and G: mitochondrial DNA (mtDNA) copy number (F) and CSA (G) in aortas (n = 8). *P < 0.05 vs. SED; ns, Not significant.

Fig. 2.

Vascular indexes of antioxidant capacity following exercise training. A and B: manganese superoxide dismutase (MnSOD) protein expression normalized to GAPDH. C: reactive oxygen species (ROS) estimated by 2′,7′-dichlorofluorescein diacetate (DCFDA) fluorescence in iliac/femoral artery homogenates (n = 8). *P < 0.05 vs. SED.

Fig. 3.

Vascular function and kinase-mediated signaling to endothelial nitric oxide synthase (eNOS) following exercise training. A and B: endothelium-dependent (EDR, A) and independent (EIR, B) vasorelaxation. C and D: non-receptor-mediated (NRC, C) and receptor-mediated (RC, D) vasocontraction in the absence (n = 6–7 animals each, 19–23 vessels each) or presence of nitric oxide synthase inhibition using N^G-monomethyl-l-arginine (l-NMMA) (n = 7 animals, 9 vessels). E and F: representative Western blots from iliac/femoral artery homogenates (E) and densitometric quantification as indicated (F) (n = 7–8). Data are presented as fold change relative to SED: *P < 0.05 vs. SED.