Hypoxia transiently affects skeletal muscle hypertrophy in a functional overload model

Abstract

-Hypoxia induces a loss of skeletal muscle mass, but the signaling pathways and molecular mechanisms involved remain poorly understood. We hypothesized that hypoxia could impair skeletal muscle hypertrophy induced by functional overload (Ov). To test this hypothesis, plantaris muscles were overloaded during 5, 12, and 56 days in female rats exposed to hypobaric hypoxia (5,500 m), and then, we examined the responses of specific signaling pathways involved in protein synthesis (Akt/mTOR) and breakdown (atrogenes). Hypoxia minimized the Ov-induced hypertrophy at days 5 and 12 but did not affect the hypertrophic response measured at day 56. Hypoxia early reduced the phosphorylation levels of mTOR and its downstream targets P70 S6K and rpS6, but it did not affect the phosphorylation levels of Akt and 4E-BP1, in Ov muscles. The role played by specific inhibitors of mTOR, such as AMPK and hypoxia-induced factors (i.e., REDD1 and BNIP-3) was studied. REDD1 protein levels were reduced by overload and were not affected by hypoxia in Ov muscles, whereas AMPK was not activated by hypoxia. Although hypoxia significantly increased BNIP-3 mRNA levels at day 5, protein levels remained unaffected. The mRNA levels of the two atrogenes MURF1 and MAFbx were early increased by hypoxia in Ov muscles. In conclusion, hypoxia induced a transient alteration of muscle growth in this hypertrophic model, at least partly due to a specific impairment of the mTOR/P70 S6K pathway, independently of Akt, by an undefined mechanism, and increased transcript levels for MURF1 and MAFbx that could contribute to stimulate the proteasomal proteolysis.

Emerging role for regulated in development and DNA damage 1 (REDD1) in the regulation of skeletal muscle metabolism

“…Accordingly, it was shown that a single bout of electrically induced eccentric muscle contractions was sufficient to reduce REDD1 protein both 30 min and 4 h postexercise in the tibialis anterior (48) and at 4 h in the gastrocnemius of male mice (117). These findings are in contrast to a report that failed to show a change in REDD1 protein in the plantaris muscle of female Wistar rats 5 days after muscle overload produced by synergistic ablation (14) or those data described above in humans. Furthermore, REDD1 was shown to be increased in the plantaris of male mice 14 days after synergistic ablation-induced muscle overload (115).…”

“…A loss of muscle mass may also be seen in response to chronic hypoxia, which can be produced physiologically (e.g., high altitude) or result from an underlying disease state such as chronic obstructive pulmonary disorder (COPD). Though REDD1 was first identified as a hypoxiainducible factor in nonmuscle cells, it has since been shown that hypoxia is sufficient to increase REDD1 mRNA and protein in skeletal muscle of animals and humans alike (13,14,20,35). Furthermore, the loss of muscle mass during hypoxia may be due to an impairment in mTORC1 activity and protein synthesis, as REDD1 protein is required for the hypoxiainduced decrease in the phosphorylation of p70S6K1 (Thr 389 ) in MEFs (13).…”

“…Muscle overload may be a viable therapeutic intervention to offset the loss of muscle mass, as overload of the plantaris muscle in female rats effectively prevented the hypoxia-induced increase in REDD1 protein expression (14). Furthermore, the relative phosphorylation (singular) of p70S6K1 (Thr 389 ) and 4E-BP1 (Thr 37/46 ) was not altered by hypoxia in the overloaded muscle.…”

Increased oxidative stress and anaerobic energy release, but blunted Thr172-AMPKα phosphorylation, in response to sprint exercise in severe acute hypoxia in humans

“…In cell cultures, hypoxia and anoxia increase Thr 172 -AMPK␣ phosphorylation more through the release of free radicals than through an increase in the AMP-to-ATP ratio (15). In contrast, chronic hypoxia (5 and 12 days of exposure to 5,500 m above sea level) did not increase skeletal muscle Thr 172 -AMPK␣ phosphorylation in rats (10). The influence of the inspired O 2 fraction (FI O 2 ) on exerciseinduced Thr 172 -AMPK␣ phosphorylation has been scarcely studied in humans (63).…”

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

“…We recently observed that hypoxia blocked IGF-1-mediated activation of the Akt/mTOR pathway in C2C12 myotubes [115]. On the contrary, the expression of myostatin, a muscle-secreted factor which reduces muscle mass through inhibition of the Akt/mTOR pathway [116,117], is increased by hypoxia exposure [106,118,119]. Inhibition of myostatin signaling (antibody administration, receptor inhibition or genetic ablation) partly prevents muscle atrophy under hypoxic conditions, further demonstrating that myostatin contributes to hypoxia-mediated muscle wasting [105,119].…”