Long Noncoding RNA lncMUMA Reverses Established Skeletal Muscle Atrophy following Mechanical Unloading

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.

Muscle unloading: A comparison between spaceflight and ground‐based models

“…The loss of muscle force‐generating capacity associated with mechanical unloading is well established (Table ). Thus, numerous studies show that HU results in a reduced force‐generating capacity of the hindlimb muscles in rats and mice . Muscle weakness is partly because of reduced muscle mass but defect in the intrinsic force‐generating capacity of skeletal muscle also contributes.…”

“…Thus, numerous studies show that HU results in a reduced force-generating capacity of the hindlimb muscles in rats and mice. [56][57][58][59][60] Muscle weakness is partly because of reduced muscle mass but defect in the intrinsic force-generating capacity of skeletal muscle also contributes. These findings are translated to single muscle fibres, which show reduction in the force/cross-sectional area (specific force) during muscle unloading.…”

Roles of lncRNAs and circRNAs in regulating skeletal muscle development

“…36 lnc-MD and lnc-mg act as ceRNAs to sequester miR-125b, leading to increased insulin-like growth factor 2 (IGF2) expression and promoting muscle differentiation in cattle or mouse, accordingly. 40 Moreover, the lncRNA MAR1 acts as a miR-487b sponge to regulate the Wnt5a protein, resulting in promotion of muscle differentiation and regeneration. Its overexpression promotes myotube formation and the expression of myogenic regulatory factors, and inhibits C2C12 myoblast proliferation.…”

“…39 In addition, mechanical unloading-induced muscle atrophy-related lncRNA (lnc-MUMA) promotes myogenic differentiation by functioning as an miR-762 sponge to regulate the core myogenic regulator, MyoD, in vitro. 40 Moreover, the lncRNA MAR1 acts as a miR-487b sponge to regulate the Wnt5a protein, resulting in promotion of muscle differentiation and regeneration. 41 In addition to the above ceRNA mechanism, some lncRNAs regulate gene expression in cis or trans.…”

Targeted overexpression of the long noncoding RNA ODSM can regulate osteoblast function in vitro and in vivo

“…With an increasing number of noncoding RNAs found to regulate many pathological processes, the value of miRNAs and lncRNAs as therapeutic targets in many diseases has received increasing attention [28][29][30] . Intervention with the expression of miRNAs or lncRNAs in vivo also had an impressive therapeutic effect in the diseases caused by mechanical unloading.…”