| First Author | Hamoudi D | Year | 2020 |
| Journal | Hum Mol Genet | Volume | 29 |
| Issue | 3 | Pages | 483-494 |
| PubMed ID | 31943048 | Mgi Jnum | J:288257 |
| Mgi Id | MGI:6416651 | Doi | 10.1093/hmg/ddz312 |
| Citation | Hamoudi D, et al. (2020) Muscle weakness and selective muscle atrophy in osteoprotegerin-deficient mice. Hum Mol Genet 29(3):483-494 |
| abstractText | Bone and muscle are tightly coupled and form a functional unit under normal conditions. The receptor-activator of nuclear factor kappaB/receptor-activator of nuclear factor kappaB ligand/osteoprotegerin (RANK/RANKL/OPG) triad plays a crucial role in bone remodeling. RANKL inhibition by OPG prevents osteoporosis. In contrast, the absence of OPG results in elevated serum RANKL and early onset osteoporosis. However, the impacts of OPG deletion on muscle structure and function are unknown. Our results showed that 1-, 3- and 5-month-old Opg-/- mice have reduced tibial and femoral bone biomechanical properties and higher levels of circulating RANKL. OPG-deficient mice displayed reduced locomotor activity and signs of muscle weakness at 5 months of age. Furthermore, OPG deficiency did not affect the skeletal muscles in 1- and 3-month-old mice. However, it impaired fast-twitch EDL but not slow-twitch Sol muscles in 5-month-old Opg-/- mice. Moreover, 5-month-old Opg-/- mice exhibited selective atrophy of fast-twitch-type IIb myofibers, with increased expression of atrophic proteins such as NF-kB, atrogin-1 and MuRF-1. We used an in vitro model to show that RANKL-stimulated C2C12 myotubes significantly increased the expression of NF-kB, atrogin-1 and MuRF-1. A 2-month anti-RANKL treatment starting at 3 months of age in Opg-/- mice improved voluntary activity, the ex vivo maximum specific force (sP0) of EDL muscles, and whole limb grip force performance and rescued the biomechanical properties of bone. In conclusion, the deletion of OPG and the disruption of the RANKL/OPG balance induced osteoporosis as well as the selective weakness and atrophy of the powerful fast-twitch IIb myofibers, which was partly alleviated by an anti-RANKL treatment. |
