Role of altered proteostasis network in chronic hypobaric hypoxia induced skeletal muscle atrophy

Abstract

BackgroundHigh altitude associated hypobaric hypoxia is one of the cellular and environmental perturbation that alters proteostasis network and push the healthy cell towards loss of muscle mass. The present study has elucidated the robust proteostasis network and signaling mechanism for skeletal muscle atrophy under chronic hypobaric hypoxia (CHH).MethodsMale Sprague Dawley rats were exposed to simulated hypoxia equivalent to a pressure of 282 torr for different durations (1, 3, 7 and 14 days). After CHH exposure, skeletal muscle tissue was excised from the hind limb of rats for biochemical analysis.ResultsChronic hypobaric hypoxia caused a substantial increase in protein oxidation and exhibited a greater activation of ER chaperones, glucose-regulated protein-78 (GRP-78) and protein disulphide isomerase (PDI) till 14d of CHH. Presence of oxidized proteins triggered the proteolytic systems, 20S proteasome and calpain pathway which were accompanied by a marked increase in [Ca2+]. Upregulated Akt pathway was observed upto 07d of CHH which was also linked with enhanced glycogen synthase kinase-3β (GSk-3β) expression, a negative regulator of Akt. Muscle-derived cytokines, tumor necrosis factor-α (TNF-α), interferon-ϒ (IFN-©) and interleukin-1β (IL-1β) levels significantly increased from 07d onwards. CHH exposure also upregulated the expression of nuclear factor kappa-B (NF-κB) and E3 ligase, muscle atrophy F-box-1 (Mafbx-1/Atrogin-1) and MuRF-1 (muscle ring finger-1) on 07d and 14d. Further, severe hypoxia also lead to increase expression of ER-associated degradation (ERAD) CHOP/ GADD153, Ub-proteasome and apoptosis pathway.ConclusionsThe disrupted proteostasis network was tightly coupled to degradative pathways, altered anabolic signaling, inflammation, and apoptosis under chronic hypoxia. Severe and prolonged hypoxia exposure affected the protein homeostasis which overwhelms the muscular system and tends towards skeletal muscle atrophy.

Ursolic acid ameliorates hypobaric hypoxia‐induced skeletal muscle protein loss via upregulating Akt pathway: An experimental study using rat model

“…Our previous studies reported that HH-induced skeletal muscle protein loss is multifaced signaling pathways which include proteome imbalance, free radical medicated oxidative stress and inflammation, oxidative protein modification, enhanced degradative pathway, altered anabolic signaling and apoptosis. 2,8,11 The present study for the first time, evaluated the protective effect of UA against HH-induced skeletal muscle damage and protein loss. The antioxidant, antiinflammatory activity and increased protein content via upregulation of AkT pathway by administration of UA may have beneficial effect for maintaining muscle mass under hypoxic stress.…”

“…Our previous studies reported that HH‐induced skeletal muscle protein loss is multifaced signaling pathways which include proteome imbalance, free radical medicated oxidative stress and inflammation, oxidative protein modification, enhanced degradative pathway, altered anabolic signaling and apoptosis 2,8,11 …”

“…This imbalance in protein homeostasis could be considered as the major cause of muscle protein loss 9,10 . Our latest study also concluded that chronic HH‐induced protein loss is a multifaced pathophysiological condition, regulated via multiple signaling pathways like proteome imbalance, free radical‐mediated inflammation, and impaired protein synthesis flux 11,12 …”

“…9,10 Our latest study also concluded that chronic HH-induced protein loss is a multifaced pathophysiological condition, regulated via multiple signaling pathways like proteome imbalance, free radical-mediated inflammation, and impaired protein synthesis flux. 11,12 Skeletal muscle atrophy has broad clinical impact not only at high altitude but also it occurs at sea level in several chronic diseases. Although it is a serious concern; even then limited treatment recommendations are available like physical rehabilitation, nutritional optimization, and treatment of underlying disease and that is not so effective treatments.…”

Regulation of skeletal muscle mitochondrial biogenesis by GSK-3β

“…Regarding effects of hypoxia on GSK-3β activity in muscle, literature is scarce and inconclusive. Chronic hypobaric hypoxia increased the total abundance of GSK-3β in rat skeletal muscle but GSK-3β activity or phosphorylation status was not assessed [168]. In addition, hypoxia exposure reduced the phosphorylation of GSK-3β in C2C12 myoblasts suggesting enhanced GSK-3β activity [169].…”