Diego Jaime, Lauren A. Fish, Laura A. Madigan, Chengjie Xi, Giorgia Piccoli, Madison D. Ewing, Bert Blaauw, Justin R. Fallon
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引用次数: 0
Abstract
Myofiber size regulation is critical in health, disease, and aging. MuSK (muscle-specific kinase) is a BMP (bone morphogenetic protein) co-receptor that promotes and shapes BMP signaling. MuSK is expressed at all neuromuscular junctions and is also present extrasynaptically in the mouse soleus, whose predominantly oxidative fiber composition is akin to that of human muscle. To investigate the role of the MuSK-BMP pathway in vivo, we generated mice lacking the BMP-binding MuSK Ig3 domain. These ∆Ig3-MuSK mice are viable and fertile with innervation levels comparable to wild type. In 3-month-old mice, myofibers are smaller in the slow soleus, but not in the fast tibialis anterior (TA). Transcriptomic analysis revealed soleus-selective decreases in RNA metabolism and protein synthesis pathways as well as dysregulation of IGF1-Akt-mTOR pathway components. Biochemical analysis showed that Akt-mTOR signaling is reduced in soleus but not TA. We propose that the MuSK-BMP pathway acts extrasynaptically to maintain myofiber size in slow muscle by promoting protein synthetic pathways including IGF1-Akt-mTOR signaling. These results reveal a novel mechanism for regulating myofiber size in slow muscle and introduce the MuSK-BMP pathway as a target for promoting muscle growth and combatting atrophy.
期刊介绍:
The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators.
Main areas of interest include:
-differentiation of skeletal muscle-
atrophy and hypertrophy of skeletal muscle-
aging of skeletal muscle-
regeneration and degeneration of skeletal muscle-
biology of satellite and satellite-like cells-
dystrophic degeneration of skeletal muscle-
energy and glucose homeostasis in skeletal muscle-
non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies-
maintenance of neuromuscular junctions-
roles of ryanodine receptors and calcium signaling in skeletal muscle-
roles of nuclear receptors in skeletal muscle-
roles of GPCRs and GPCR signaling in skeletal muscle-
other relevant aspects of skeletal muscle biology.
In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission.
Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.