Hypoxic Exercise, Autophagy, And Angiogenesis

Autophagy, a lysosomal recycling process, and angiogenesis, the formation of new blood vessels, are both integral for maintaining cellular health in skeletal muscle upon ascent to high altitude (HA). PURPOSE: Investigate the effects of acute hypoxia alone or in combination with aerobic exercise on markers of autophagy and angiogenesis. METHODS: In a randomized, cross-over design, seven healthy and active men (n = 4) and women (n = 3) (29 ± 5 yr, VO2 max = 41.9 ± 7.3 ml/kg/min) completed three experimental trials, consisting of a 60 min aerobic cycling exercise bout at 65% of altitude-specific VO2 max at baseline residence (BLR EX; 1585 m), in hypobaric hypoxia (HYP EX; 4300 m) and a duration-matched seated resting trial in hypobaric hypoxia (HYP REST; 4300 m). Skeletal muscle micro-biopsies of vastus lateralis were taken before (BLR), immediately post-exercise (BLR or HYP) and 3-h post-exercise (BLR) and at those same time points in HYP REST. Samples were analyzed for protein expression of primary and supporting markers of autophagy (p62, LC3 II/I, BNIP3, HSP90), angiogenesis (VEGFA, ERRα,) and HIF-1α. RESULTS: In BLR EX, p62 protein expression remained unchanged from pre- to post-exercise but decreased 3-h post-exercise (Fold Change (FC) = 0.33 ± 0.37, P = 0.0014). In HYP EX, p62 protein expression decreased from pre- to post-exercise (FC = 0.27 ± 0.14, P < 0.001), LC3 II/I increased from pre-to post exercise (FC = 3.16 ± 1.12, P = 0.0074), HSP90 decreased from pre-to post- exercise (FC = 0.13 ± 0.14, P < 0.0001) and all returned to pre-exercise values 3-h post exercise. In HYP REST, HSP90 remained unchanged from the pre-to post-exercise timepoint but decreased at the 3-h post exercise timepoint (FC = 0.33 ± 0.41, P = 0.0121). No significant differences from BLR were detected across conditions or timepoints for BNIP3, VEGFA, ERRα, and HIF-1α. CONCLUSION: These findings indicate that autophagic flux was marginally changed by exercise at low altitude or hypoxia alone, but increased with exercise combined with hypoxia. Angiogenesis appears unchanged by either exercise or hypoxia. Moreover, autophagy activation in skeletal muscle with exercise in hypoxia appears to occur without marked HIF-1α activity. Authors’ views not official U.S. Army or DoD policy. Funding: UNM COE, GPSPA, and USAMRDC UNM COE, GPSA, USAMRDC