The role of satellite cells in skeletal muscle plasticity

The regenerative capabilities of skeletal muscle allow it to grow in response to external stimulus such as load or injury. When stimulus is applied, muscle stem cells (satellite cells) proliferate and differentiate to build on existing muscle, causing hypertrophy. Many proteins are involved in facilitating this response and the role of MEGF10, a transmembrane protein involved in muscle myopathy, is still poorly understood. An in vivo mouse overload model and complimentary in vitro culture experiments were used to better understand the role of satellite cells and MEGF10 in muscle hypertrophy. Experiments on control mice showed that after 10-days overload, skeletal muscle fibres showed optimum levels of muscle hypertrophy, myonuclear accretion, and expression of the myogenic transcription factors Pax7, MyoD and myogenin. Overloading mice that were either heterozygous (Megf10+/-) or homozygous (Megf10-/-) for a MEGF10 mutation demonstrated that loss of MEGF10 significantly impaired the hypertrophy process, and resulted in impairments to the diaphragm that may affect respiration. A separate analysis of Pax3-expressing C1F myoblasts demonstrated that these cells undergo the same myogenic expression pattern as Pax7-expressing C2C12 myoblasts, and undergo enhanced fusion and differentiation on soft polydimethylsiloxane (PDMS) surfaces of a stiffness similar to muscle in vivo. In conclusion, this study has provided novel data regarding the importance of MEGF10 in hypertrophy, and highlighted its role in the expansion of muscle satellite cells that will then go on to fuse and differentiate. Additionally, a previously unreported effect on the diaphragm has been found that may serve in validating this MEGF10 knockout mouse as a translatable model of the MEGF10 myopathy, early onset myopathy, areflexia, respiratory distress and dysphagia (EMARDD). The importance of cell culture surface stiffness has also been highlighted by this study, as well as the importance of using in vitro systems to support in vivo analyses in muscle research.