Downregulation of Akt/mammalian target of rapamycin pathway in skeletal muscle is associated with increased REDD1 expression in response to chronic hypoxia

Abstract

Although it is well established that chronic hypoxia leads to an inexorable loss of skeletal muscle mass in healthy subjects, the underlying molecular mechanisms involved in this process are currently unknown. Skeletal muscle atrophy is also an important systemic consequence of chronic obstructive pulmonary disease (COPD), but the role of hypoxemia in this regulation is still debated. Our general aim was to determine the molecular mechanisms involved in the regulation of skeletal muscle mass after exposure to chronic hypoxia and to test the biological relevance of our findings into the clinical context of COPD. Expression of positive and negative regulators of skeletal muscle mass were explored 1) in the soleus muscle of rats exposed to severe hypoxia (6,300 m) for 3 wk and 2) in vastus lateralis muscle of nonhypoxemic and hypoxemic COPD patients. In rodents, we observed a marked inhibition of the mammalian target of rapamycin (mTOR) pathway together with a strong increase in regulated in development and DNA damage response 1 (REDD1) expression and in its association with 14-3-3, a mechanism known to downregulate the mTOR pathway. Importantly, REDD1 overexpression in vivo was sufficient to cause skeletal muscle fiber atrophy in normoxia. Finally, the comparative analysis of skeletal muscle in hypoxemic vs. nonhypoxemic COPD patients confirms that hypoxia causes an inhibition of the mTOR signaling pathway. We thus identify REDD1 as a negative regulator of skeletal muscle mass during chronic hypoxia. Translation of this fundamental knowledge into the clinical investigation of COPD shows the interest to develop therapeutic strategies aimed at inhibiting REDD1.

Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuli

“…In addition, at the molecular level this effect is associated with a significant induction of the MAFbx, suggesting an activation of proteasomal degradation which could contribute to a reduction in skeletal muscle mass (Gomes et al, 2001). Thus these data are in agreement with previous studies suggesting a direct effect of hypoxia per se in the induction of skeletal muscle atrophy independent of energy intake status (Bigard et al, 1996;Favier et al, 2010;Pison et al, 1998). Interestingly, comparison between H vs Npf groups showed a significant decrease in muscle weight in the SOL but not the GAS muscle (Table 1).…”

“…We further demonstrated that CoCl 2 requires the presence down-regulated in rat skeletal muscle in response to chronic hypoxia indicating that hypoxia negatively regulates protein synthesis in skeletal muscle (Favier et al, 2010). Therefore, the parallel actions of myostatin and hypoxia on protein synthesis suggest that induction of myostatin by hypoxia could represent a potential mechanism for hypoxia-induced atrophy.…”

“…In addition, the decrease in muscle mass at high altitude is associated with an anorexic effect. However, even when the anorexic effect is controlled using pair feed experimental design the decrease in muscle mass is observed indicating that part of hypoxia-induced skeletal muscle atrophy is independent of undernutrition associated with hypoxia (Bigard et al, 1996;Favier et al, 2010;Pison et al, 1998). Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation.…”

Hypoxia and Resistance Exercise: A Comparison of Localized and Systemic Methods

“…Previous research has demonstrated that chronic exposure to hypoxia adversely affects protein kinase B/mTOR signalling [123], up-regulates myostatin expression [124], and subsequently leads to atrophy in skeletal muscle [125].…”

Hypoxia transiently affects skeletal muscle hypertrophy in a functional overload model

“…Muscle atrophy has already been observed in humans after expeditions in high altitude (44), while a reduction in muscle growth has been shown in rodents chronically exposed to hypobaric hypoxia (7,16). In vitro studies showed that the Akt/mTOR pathway could be inhibited by hypoxia exposure (12,27,31), but to our knowledge, only few in vivo studies reported that prolonged hypoxia exposure altered this signaling pathway in skeletal muscles (16). Myostatin, a mediator of muscle atrophy, has been shown to partly account for the hypoxia-induced effects on muscle mass (20).…”