Distinct responses of protein turnover regulatory pathways in hypoxia- and semistarvation-induced muscle atrophy

Abstract

de Theije CC, Langen RC, Lamers WH, Schols AM, Köhler SE. Distinct responses of protein turnover regulatory pathways in hypoxia-and semistarvation-induced muscle atrophy. Am J Physiol Lung Cell Mol Physiol 305: L82-L91, 2013. First published April 26, 2013 doi:10.1152/ajplung.00354.2012.-The balance of muscle protein synthesis and degradation determines skeletal muscle mass. We hypothesized that hypoxia-induced muscle atrophy and alterations in the regulation of muscle protein turnover include a hypoxia-specific component, in addition to the observed effects of reduction in food intake in response to hypoxia. Mice were subjected to normoxic, hypoxic (8% oxygen), or pair-fed conditions for 2, 4, and 21 days. Cell-autonomous effects of hypoxia on skeletal muscle were also assessed in differentiated C2C12 myotubes. Hypoxia induced an initial rapid loss of body and muscle weight, which remained decreased during chronic hypoxia and could only in part be explained by the hypoxia-induced reduction of food intake (semistarvation). Regulatory steps of protein synthesis (unfolded protein response and mammal target of rapamycin signaling) remained active in response to acute and sustained hypoxia but not to semistarvation. Activation of regulatory signals for protein degradation, including increased expression of Murf1, Atrogin-1, Bnip3, and Map1lc3b mRNAs, was observed in response to acute hypoxia and to a lesser extent following semistarvation. Conversely, the sustained elevation of Atrogin-1, Bnip3, and Map1lc3b mRNAs and the increased activity of their upstream transcriptional regulator Forkhead box O1 were specific to chronic hypoxia because they were not observed in response to reduced food intake. In conclusion, altered regulation of protein turnover during hypoxia-induced muscle atrophy resulted from an interaction of semistarvation and a hypoxia-specific component. The finding that food restriction but not hypoxia-induced semistarvation inhibited regulatory steps in protein synthesis suggests a hypoxiaspecific impairment of the coordination between protein-synthesis signaling and protein-degradation signaling in skeletal muscle. hypoxia; mouse model; protein turnover; regulation; skeletal muscle WEIGHT LOSS AND MUSCLE ATROPHY are common features in advanced chronic obstructive pulmonary disease (COPD). In addition to nutritional imbalance, systemic inflammation, and progressive inactivity, hypoxemia has been implicated as a trigger for muscle atrophy in patients with COPD. Hypoxemia is a symptom during the whole course of the disease with chronic hypoxemia in end-stage COPD and acute hypoxemic episodes during exacerbations (50). Understanding the mechanisms by which hypoxia induces muscle atrophy will benefit the treatment of this disease because loss of muscle mass is a strong predictor of mortality and significantly increases disease burden (8,17,25,35,57). Although exposure to hypobaric hypoxia at high-altitudes results in muscle atrophy in men and animals (5,11,21,23), it is still under debate whether hypoba...

HIF-1-driven skeletal muscle adaptations to chronic hypoxia: molecular insights into muscle physiology

“…Some works reported an increase in MAFbx mRNA [74,119], while this expression in not always observed after prolonged exposure [101,123]. The other well studied E3 ligase MuRF1 presents a similar expression pattern with an increase during the first week of hypoxia exposure [74,123] and a return to basal level during longer exposure [101,123]. These patterns of MuRF1 and MAFbx expression in response to hypoxia are similar to those reported during unloading and muscle inactivity [129].…”

“…While this negative influence was thought to be primarily related to cold exposure, high energy expenditure and especially hypophagia [99], we and others have demonstrated that hypoxia per se accounts for skeletal muscle atrophy [74,100,101]. Although numerous differences exist between studies (altitude level, normobaric vs. hypobaric hypoxia, exposure duration, age of animals and acclimatization duration), analysis of published data clearly shows a significant positive correlation between hypoxia severity and the level of muscle atrophy in rats (Fig.…”

“…Kinetics is likely of particular importance when studying these markers. Some works reported an increase in MAFbx mRNA [74,119], while this expression in not always observed after prolonged exposure [101,123]. The other well studied E3 ligase MuRF1 presents a similar expression pattern with an increase during the first week of hypoxia exposure [74,123] and a return to basal level during longer exposure [101,123].…”

“…Autophagy is a process involving the formation of autophagosomes and this mechanism is initiated by the dissociation of the Beclin1/Bcl-2 complex. HIF-1 mediates the increase in BNIP3 expression during hypoxia exposure in skeletal muscle [72][73][74]. BNIP3 competes with Beclin1 for binding to Bcl-2 leading to the release of Beclin1 [75], thus promoting the initiation of autophagy and mitophagy.…”

“…Protein translation could also be down-regulated in a TORC1-independent way via the inhibition of the initiation factor eIF2. While eIF2-related inhibition of protein synthesis has been well characterized in tumorigenic cells [128], the few studies investigating such a mechanism in skeletal muscle do not support this hypothesis [74,125].…”