Abstract
Myoferlin (MyoF), which is a calcium/phospholipid-binding protein expressed in cardiac and muscle tissues, belongs to the ferlin family. While MyoF promotes myoblast differentiation, the underlying mechanisms remain poorly understood. Here, we found that MyoF not only promotes C2C12 myoblast differentiation, but also inhibits muscle atrophy and autophagy. In the present study, we found that myoblasts fail to develop into mature myotubes due to defective differentiation in the absence of MyoF. Meanwhile, MyoF regulates the expression of atrophy-related genes (Atrogin-1 and MuRF1) to rescue muscle atrophy. Furthermore, MyoF interacts with Dishevelled-2 (Dvl-2) to activate canonical Wnt signaling. MyoF facilitates Dvl-2 ubiquitination resistance by reducing LC3-labeled Dvl-2 levels and antagonizing the autophagy system. In conclusion, we found that MyoF plays an important role in myoblast differentiation during skeletal muscle atrophy. At the molecular level, MyoF protects Dvl-2 against autophagy-mediated degradation, thus promoting activation of the Wnt/β-catenin signaling pathway. Together, our findings suggest that MyoF, through stabilizing Dvl-2 and preventing autophagy, regulates Wnt/β-catenin signaling-mediated skeletal muscle development.
Highlights
Autophagy, including macroautophagy, microautophagy, and chaperone-mediated autophagy, was first described in 1963 [1]
Increased MyoF expression was accompanied by increased myosin heavy chain (MyHC) expression during C2C12 myoblast differentiation (Figure 1c,d)
MyoF has been proven to be the pathogenic gene of muscular dystrophy, its antagonism against autophagy by stabilizing Dvl-2 has not yet been determined
Summary
Autophagy, including macroautophagy, microautophagy, and chaperone-mediated autophagy, was first described in 1963 [1]. Autophagy refers to the encapsulation of cytoplasmic components, such as proteins and organelles, destined for transport to lysosomes for degradation [2]. Under stress conditions, such as starvation and hypoxia, autophagy is activated to promote cell survival by releasing energy substrates through degradation of cellular components and elimination of defective or damaged organelles [3]. Skeletal muscle is composed of highly organized myofibers and its lean mass provides a tissue amino acid source that can be used under conditions of stress or starvation [5]. The ubiquitin-proteasomal pathway and the autophagic/lysosomal pathway are two highly conserved pathways mediating protein degradation in skeletal muscle [6]. In the ubiquitin-proteasomal pathway, ubiquitin-tagged proteins are degraded in the proteasome complex after conjugation with multiple ubiquitin moieties [7]
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