Control of skeletal muscle mass by Bone Morphogenetic proteins – BMP-MyoMass

Growth, homeostasis and regeneration of skeletal muscle mass depend on the presence of muscle stem cells, their ability to generate muscle fibres as well as the subsequent increase in muscle fibre size. Importantly, correct muscle function requires correct cellular composure of skeletal muscle during growth and regeneration. Understanding the regulation of muscle mass formation and the characterisation of involved signalling molecules are fundamental steps towards the development of regenerative medicine for skeletal muscle diseases such as muscular dystrophies or ageing related sarcopenia.

Previous work of the participants of this proposal demonstrated that Bone Morphogenetic Proteins (BMPs), diffusible morphogens of the TGF-ß family of signalling molecules, and their antagonist Noggin regulate proliferation, differentiation and self-renewal of muscle stem cells. Preliminary data furthermore demonstrate that BMP-signalling determines the size of adult skeletal muscle fibres, is required for their regeneration following myoinjury and protects muscle fibres from disease induced muscle wasting. Here we hypothesise that BMPs and antagonist proteins establish a signalling network, which serves not only for muscle stem cells to communicate amongst each other but also for the interaction between muscle stem cells and differentiated myofibres. We hypothesise that this signalling network defines the rate of muscle growth, final muscle size and number of muscle stem cells inherent to adult skeletal muscle. We hypothesise that the signalling properties of BMPs maintains the muscle mass in homeostasis and thereby defines skeletal muscle function during normal development and disease conditions.

The main aims of the proposed research project are:
• Determine the expression profile of BMP-signalling pathway components in skeletal muscle progenitors and terminally differentiated muscle cells.
• Determine the cell-autonomous and non cell-autonomous function of the BMP-signalling pathway in muscle progenitors in vitro and in vivo.
• Determine the role of BMP signalling on growth and function of differentiated skeletal muscle.
• Understand the role of BMP signalling during muscle atrophy and during muscle regeneration.

Expected results will decipher the molecular mechanisms how BMPs regulate muscle size and function. We will be able to conclude on the potential therapeutic targets of the BMP signalling pathway for strategies that aim to improve muscle growth and muscle regeneration in the context of muscle pathologies or injuries.