Delayed denervation-induced muscle atrophy in Opg knockout mice

Abstract

Recent evidence has shown a crucial role for the osteoprotegerin/receptor activator of nuclear factor κ-B ligand/RANK (OPG/RANKL/RANK) signaling axis not only in bone but also in muscle tissue; however, there is still a lack of understanding of its effects on muscle atrophy. Here, we found that denervated Opg knockout mice displayed better functional recovery and delayed muscle atrophy, especially in a specific type IIB fiber. Moreover, OPG deficiency promoted milder activation of the ubiquitin-proteasome pathway, which further verified the protective role of Opg knockout in denervated muscle damage. Furthermore, transcriptome sequencing indicated that Opg knockout upregulated the expression of Inpp5k, Rbm3, and Tet2 and downregulated that of Deptor in denervated muscle. In vitro experiments revealed that satellite cells derived from Opg knockout mice displayed a better differentiation ability than those acquired from wild-type littermates. Higher expression levels of Tet2 were also observed in satellite cells derived from Opg knockout mice, which provided a possible mechanistic basis for the protective effects of Opg knockout on muscle atrophy. Taken together, our findings uncover the novel role of Opg in muscle atrophy process and extend the current understanding in the OPG/RANKL/RANK signaling axis.

Epigenetic control of skeletal muscle atrophy

“…revealed that Tet2 deficiency compromises the regenerative ability and myotube fusion in skeletal muscle [ 64 ]. Strategies aimed at enhancing Tet2 stability or ensuring its elevated expression have been shown to reduce the effects of denervation-induced muscle atrophy and improve skeletal muscle function in the context of obesity [ 65 , 66 ]. Further investigation has shown that Tet2 deficiency disrupts the proliferation and differentiation of SCs, a process mediated by the calcium signaling gene Slc8a3 and Myog , a critical regulator of myogenesis [ 63 , 64 ].…”