Pathomechanisms in Facioscapulohumeral muscular dystrophy

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Diseases can be treated more effectively if the causes/mechanisms underlying the symptoms are known. For muscular dystrophy, the causative defect is changes in genes or DNA that in turn, produce changes to proteins. However, it is generally poorly understood how such defects result in the debilitating, progressive skeletal muscle weakness and wasting typical of muscular dystrophies. Every cell in the body contains the same DNA, which is divided into genes, each of which carries the instructions to make a protein(s): the molecules that build, maintain and operate the body. The selection of genes that are expressed (active) in a particular cell type, such as in a muscle fibre, dictate which proteins are made. This gives the cell its special characteristics and functions. For example, specific muscle genes are not expressed in skin cells, and vice-versa.Facioscapulohumeral muscular dystrophy (FSHD) is incurable. FSHD is caused by a change in a particular region of DNA that leads to production of a protein called DUX4, that is not normally present in muscle. DUX4 is a 'transcription factor' meaning that it can control the expression of other genes by binding to their regulatory regions, and so can alter the type of proteins that are made by a cell. Thus the carefully coordinated pattern of gene expression and protein production that enables skeletal muscle to function effectively is perturbed by the presence of DUX4. This ultimately leads to muscle weakness and wasting.We have examined gene expression changes in FSHD and DUX4-expressing muscle cells and used mathematical tools to understand which signalling process are perturbed. We found that pathways are suppressed that control generation of mitochondria and processes associated with mitochondrial function such as dealing with by-products of metabolism/respiration called reactive oxygen species (that cause oxidative stress). It is known that FSHD muscle cells are more sensitive to oxidative stress, and a recent clinical trial (clinicaltrials.gov number: NCT01596803) reported that administration of anti-oxidants, improved aspects of muscle function in FSHD patients.Muscle metabolism is carefully coordinated to ensure generation of enough energy to make muscle always work efficiently, from when resting to undergoing strenuous exercise. These systems are perturbed in FSHD but it is unclear how DUX4 does this. To investigate, we will examine the rate of metabolism (using a technique called respirometry), changes in gene expression (using a technique called RNA-Sequencing) and metabolism (using a technique called Nuclear magnetic resonance (NMR)) in FSHD cells and cells made to express DUX4. This will give a better understanding of the cause of FSHD, with the long-term aim of finding new and more effective targeted therapies for FSHD to inform, support and underpin clinical trials.