Abstract
Reversing established muscle atrophy following mechanical unloading is of great clinical challenge. Long noncoding RNAs (lncRNAs) have been demonstrated to play important roles in myogenesis. Here we identified a lncRNA (mechanical unloading-induced muscle atrophy-related lncRNA [lncMUMA]) enriched in muscle, which was the most downregulated lncRNA during muscle atrophy development in hindlimb suspension (HLS) mice. The in vitro and in vivo data demonstrated that the decreased expression levels of lncMUMA closely associated with a reduction of myogenesis during mechanical unloading. Mechanistically, lncMUMA promoted myogenic differentiation by functioning as a miR-762 sponge to regulate the core myogenic regulator MyoD in vitro. The enforced expression of lncMUMA relieved the decreases in MyoD protein and muscle mass in miR-762 knockin mice. Therapeutically, the enforced expression of lncMUMA improved the in vitro myogenic differentiation of myoblasts under microgravity simulation, prevented the muscle atrophy development, and reversed the established muscle atrophy in HLS mice. These findings identify lncMUMA as an anabolic regulator to reverse established muscle atrophy following mechanical unloading.
Highlights
Mechanical unloading induces obvious skeletal muscle atrophy and functional deficit, especially under microgravity environment during spaceflight
We show that the enforced expression of lncMUMA improved the in vitro myogenic differentiation of myoblasts under microgravity simulation, prevented the muscle atrophy development, and reversed the established muscle atrophy in hindlimb suspension (HLS) mice
LncRNAs, including H19,12,13 linc-MD1,14 Yam-1,17 Malat[1,16] and lnc-mg,[15] have been demonstrated to regulate muscle differentiation, while little is known about their function during myogenesis in vivo
Summary
Mechanical unloading induces obvious skeletal muscle atrophy and functional deficit, especially under microgravity environment during spaceflight. Exposure to microgravity for 3–6 months induces skeletal muscle atrophy with more than 40% impairment of functional properties in astronauts during spaceflight.[1,2] Decreased muscle differentiation and protein synthesis are largely responsible for the mechanical unloading-induced skeletal muscle atrophy.[3,4] to date there are no effective countermeasures to combat the mechanical unloading-induced skeletal muscle atrophy. Exercises are used to replace mechanical loads during spaceflight. Astronauts on the international space station spend 5 hr/week for aerobic exercise and 3–6 days/week for resistance exercise;[5] the exercises are insufficient to prevent loss of muscle strength and endurance.[2]
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