Rab44 deficiency accelerates recovery from muscle damage by regulating mTORC1 signaling and transport of fusogenic regulators

Abstract

The skeletal muscle is a tissue that shows remarkable plasticity to adapt to various stimuli. The development and regeneration of skeletal muscles are regulated by numerous molecules. Among these, we focused on Rab44, a large Rab GTPase, that has been recently identified in immune cells and osteoclasts. Recently, bioinformatics data has revealed that Rab44 is upregulated during the myogenic differentiation of myoblasts into myotubes in C2C12 cells. Thus, Rab44 may be involved in myogenesis. Here, we have investigated the effects of Rab44 deficiency on the development and regeneration of skeletal muscle in Rab44 knockout (KO) mice. Although KO mice exhibited body and muscle weights similar to those of wild‐type (WT) mice, the histochemical analysis showed that the myofiber cross‐sectional area (CSA) of KO mice was significantly smaller than that of WT mice. Importantly, the results of muscle regeneration experiments using cardiotoxin revealed that the CSA of KO mice was significantly larger than that of WT mice, suggesting that Rab44 deficiency promotes muscle regeneration. Consistent with the in vivo results, in vitro experiments indicated that satellite cells derived from KO mice displayed enhanced proliferation and differentiation. Mechanistically, KO satellite cells exhibited an increased mechanistic target of rapamycin complex 1 (mTORC1) signaling compared to WT cells. Additionally, enhanced cell surface transport of myomaker and myomixer, which are essential membrane proteins for myoblast fusion, was observed in KO satellite cells compared to WT cells. Therefore, Rab44 deficiency enhances muscle regeneration by modulating the mTORC1 signaling pathway and transport of fusogenic regulators.

Rab44 negatively regulates myoblast differentiation by controlling fusogenic protein transport and mTORC1 signaling

“…However, in the muscle-injury regeneration model, the muscle fiber cross-sectional area of Rab44-deficient mice was significantly larger than that of the wild-type mice. 43 Thus, it is likely that Rab44-deficient skeletal muscles exhibit enhanced regenerative activity after injury in vivo.…”

Unveiling the Potential of Nelumbo nucifera-Derived Liensinine to Target The Myostatin Protein and to Counteract Muscle Atrophy

“…An inverted microscope (Olympus IX83, Olympus Co., Japan) was used to take pictures of the stained sections. The myofiber cross-sectional area (CSA) was determined by analyzing at least 100 fibers per gastrocnemius muscle sample, and the average CSA was calculated, as described previously . In brief, the calculation of the CSA involves image acquisition, automated segmentation, and CSA measurement using calibrated scales.…”