Fifteen days of 3,200 m simulated hypoxia marginally regulates markers for protein synthesis and degradation in human skeletal muscle

Abstract

Chronic hypoxia leads to muscle atrophy. The molecular mechanisms responsible for this phenomenon are not well defined in vivo. We sought to determine how chronic hypoxia regulates molecular markers of protein synthesis and degradation in human skeletal muscle and whether these regulations were related to the regulation of the hypoxia-inducible factor (HIF) pathway. Eight young male subjects lived in a normobaric hypoxic hotel (FiO2 14.1%, 3,200 m) for 15 days in well-controlled conditions for nutrition and physical activity. Skeletal muscle biopsies were obtained in the musculus vastus lateralis before (PRE) and immediately after (POST) hypoxic exposure. Intramuscular hypoxia-inducible factor-1 alpha (HIF-1α) protein expression decreased (−49%, P=0.03), whereas hypoxia-inducible factor-2 alpha (HIF-2α) remained unaffected from PRE to POST hypoxic exposure. Also, downstream HIF-1α target genes VEGF-A (−66%, P=0.006) and BNIP3 (−24%, P=0.002) were downregulated, and a tendency was measured for neural precursor cell expressed, developmentally Nedd4 (−47%, P=0.07), suggesting lowered HIF-1α transcriptional activity after 15 days of exposure to environmental hypoxia. No difference was found on microtubule-associated protein 1 light chain 3 type II/I (LC3b-II/I) ratio, and P62 protein expression tended to increase (+45%, P=0.07) compared to PRE exposure levels, suggesting that autophagy was not modulated after chronic hypoxia. The mammalian target of rapamycin complex 1 pathway was not altered as Akt, mammalian target of rapamycin, S6 kinase 1, and 4E-binding protein 1 phosphorylation did not change between PRE and POST. Finally, myofiber cross-sectional area was unchanged between PRE and POST. In summary, our data indicate that moderate chronic hypoxia differentially regulates HIF-1α and HIF-2α, marginally affects markers of protein degradation, and does not modify markers of protein synthesis or myofiber cross-sectional area in human skeletal muscle.

Severe energy deficit at high altitude inhibits skeletal muscle mTORC1‐mediated anabolic signaling without increased ubiquitin proteasome activity

“…There were also no differences between phases in the enzymatic activities of the catalytic subunits of the 26S proteasome, an additional indication that muscle proteolysis was not significantly influenced by HA or the combination of chronic HA and severe energy deficit. In agreement with findings from our study, MuRF1 mRNA expression was lower in humans who were exposed to HA at 3200 m for 15 d compared with SL, with no other changes in the markers of proteolysis between phases (50). Similarly, D'Hulst et al previously reported lower postprandial 26S proteasome activity under acute HA conditions compared with SL (49).…”

“…By d 21, chronic HA exposure while being severely underfed manifested in a complete suppression of mTORC1mediated anabolic signaling in response to both exercise and protein ingestion. Two previous human investigations (50,51) reported little or no change in mTORC1-mediated anabolic signaling under basal conditions after 7-15 d of altitude exposure at 3200-4600 m, but, to the best of our knowledge, no human study has examined the acute anabolic signaling response to exercise and protein feeding after chronic HA exposure combined with severe energy deficit. Several investigations, using stable isotope methodologies, have consistently demonstrated that shortterm (,21 d) moderate energy deficit (;20-40%) reduces rates of basal skeletal muscle protein synthesis (13)(14)(15)(16)(17) and blunts synthetic response to a protein-containing meal (17,18) at SL.…”

Panax notoginseng saponins mitigate cisplatin induced nephrotoxicity by inducing mitophagy via HIF-1α

“…In hypoxic conditions, HIF-1α migrates to the nucleus and transcribes target genes such as BNIP3 [ 28 ]. Therefore, increased BNIP3 expression indicates enhanced transcriptional activity of HIF-1α [ 29 – 31 ]. We observed increased BNIP3 mRNA (Figure 7 ) and protein (Figure 8 ) levels in the cisplatin treatment group.…”

Repeated maximal‐intensity hypoxic exercise superimposed to hypoxic residence boosts skeletal muscle transcriptional responses in elite team‐sport athletes

“…vascular endothelial growth factor (VEGF; ‐66%)] (D'Hulst et al . ), absence of muscle angiogenesis as well as marginal changes in oxidative enzymes [e.g. citrate synthase (CS)] (Lundby et al .…”

“…Specifically, downregulation of HIF-1a (-49%) and its target genes [e.g. vascular endothelial growth factor (VEGF; -66%)] (D'Hulst et al 2016), absence of muscle angiogenesis as well as marginal changes in oxidative enzymes [e.g. citrate synthase (CS)] (Lundby et al 2009) have been reported.…”