Skeletal muscles are dynamic mechanical and metabolic machines that drive body movement and energy expenditure. Skeletal muscles are dynamic tissues that can adapt quickly to alterations in mechanical unloading by altering their mass and muscle fiber cross-sectional area. Skeletal muscle strength and endurance are essential to the health, well-being, and performance of astronauts during spaceflight and upon return to a gravitational environment. The mechanical unloading due to the microgravity (#G) of spaceflight causes muscle fiber atrophy and fiber-type shift of postural muscles in the lower extremities and flexors in the upper extremities. Microgravity also increases the risk of skeletal muscle damage, weakness, and thus the risk of injury upon reloading (e.g., EVAs, Mars).
Specific Aim 1:
We will test the hypothesis that a cyclophilin A-Nox2 pathway is causal in translocation of nNOSµ, muscle fiber atrophy, and fiber-type shift during µG. We postulate that cyclophilin A is upstream of Nox2 assembly and activation. Peptidyl inhibition, pharmacological intervention, and gene knockdown will be used as countermeasures.
Specific Aim 2:
We hypothesize that acid sphingomyelinase upregulates ceramide and assists Nox2 assembly in unloaded skeletal muscle. We postulate that inhibition of ASMase via etidronate and siRNA will also mitigate muscle fiber atrophy and fiber-type shift from slow to fast-twitch.
Specific Aim 3:
We hypothesize that ROS produced by Nox2 activation during mechanical unloading impede an AktmTOP signaling pathway activating 4EBP1, but not p70S6K, and thus protein synthesis. A specific peptide inhibitor (gp91ds-tat) will be used to test that hypothesis.
This experiment is currently in progress. Results will be available at the conclusion of the study