Oxidative protein modification alters proteostasis under acute hypobaric hypoxia in skeletal muscles: a comprehensive in vivo study

Abstract

While numerous maladies are associated with hypobaric hypoxia, muscle protein loss is an important under studied topic. Hence, the present study was designed to investigate the mechanism of muscle protein loss at HH. SD rats were divided into normoxic rats, while remaining rats were exposed to simulated hypoxia equivalent to 282-torr pressure (equal to an altitude of 7620 m, 8% oxygen), at 25 °C for 6, 12, and 24 h. Post-exposure rats were sacrificed and analysis was performed. Ergo, muscle loss-related changes were observed at 12 and 24 h post-HH exposure. An increased reactive oxygen species production and decreased thiol content was observed in HH-exposed rats. This disturbance caused substantial protein oxidative modification in the form of protein carbonyl content and advanced oxidation protein products. The analysis showed increase levels of bityrosine, oxidized tryptophan, lysine conjugate, lysine conjugate with MDA, protein hydroperoxide, and protein-MDA product. These changes were also in agreement with increase in lipid hydroperoxides and MDA content. HSP-70 and HSP-60 were upregulated significantly, and this finding is corroborated with increase in ER stress biomarker, GRP-78. Overloading of cells with misfolded proteins further activated degradative machinery. Consequently, pro-apoptotic signaling cascade, caspase-3, and C/EBP homologous protein were also activated in 24-h HH exposure. Release of tryptophan and tyrosine was also increased with 24-h HH exposure, indicated protein degradation. Elevation in resting intracellular calcium ion, [Ca]i, was also observed at 12- and 24-h HH exposure. The present study provides a detailed mechanistic representation of muscle protein loss during HH exposure.

Cisplatin-Induced Skeletal Muscle Dysfunction: Mechanisms and Counteracting Therapeutic Strategies

“…Intracellular Ca 2+ overload can be considered a cause of the increased protein degradation and muscle atrophy characterizing cisplatin-induced cachexia. Indeed, increased intracellular Ca 2+ activates calpains, calcium-activated proteases, that play a pivotal role in the initiation of most proteolytic pathways such as the ubiquitin-proteasome pathway [43]. Furthermore, several studies show that intracellular calcium increase stimulates the mitochondrial apoptotic process through the activation of proapoptotic protein Bax which favors the formation of the mitochondrial permeability transition pore (mPTP) allowing the release of cytochrome C from mitochondria and promoting cell apoptosis [44].…”

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

“…Shreds of evidence from past studies suggested that an altitude of 5000m and higher (Everest Base camp) led to the considerable deterioration of skeletal muscle tissue [ 1 ]. Our recent study also provided the detailed overview of oxidative protein modification in response to hypobaric hypoxia, which altered muscle protein homeostasis and triggered ER stress [ 2 ]. Although the acute hypoxia exposure was activating several proteolytic pathways, studies have established that prolonged stay at high altitude leads to loss of skeletal muscle mass and a decline in physical performance [ 3 , 4 ].…”

Thiamine diphosphate synthesis and redox state indicator in rat brain during of B(1) hypovitaminosis

“…It can be assumed that under these conditions, TPK activity and immunoreactivity decrease (Fig. 6, B) is partly a consequence of the protein modification due to changes the intracellular redox state [26,27]. These changes are reversible and, as can be seen from the data presented, even with a single thiamine administration, redox state normalization was observed.…”