Do lamin A/C and emerin mutations in satellite cells contribute to Emery-Driefuss muscular dystrophy?

Muscle is made of thousands of muscle fibres, which are repaired and regenerated by muscle stem cells called satellite cells. Muscular dystrophies are a group of inherited disorders that are characterised by progressive muscle weakness and degeneration. Since muscle is responsible for movement, its gradual loss in muscular dystrophies can severely affect the quality of life of a patient, and in some disorders, drastically shorten their lifespan. Compromised satellite cell function is thought to contribute to loss of muscle in some of these conditions, including Emery-Dreifuss muscular dystrophy (EDMD). It has been shown that EDMD is caused by problems in genes that make proteins involved in maintaining a healthy nucleus. We intend to examine satellite cells from patients suffering from EDMD to understand how these mutated proteins affected their function and so muscle repair. We will also use mouse models of the disease to study satellite cell biology. Findings on mouse satellite cells should be broadly applicable to man. Theoretically, manipulation of satellite cells could both augment and prolong muscle function in people with muscular dystrophy, which also has the advantage of maintaining a muscle environment still capable of responding to other forms of therapy.

Autosomal Emery-Dreifuss muscular dystrophy (A-EDMD) is caused by mutations in the LMNA gene, that encodes four intermediate filament-like proteins, the major being lamin A and C. Together with B-type lamins, they form part of a proteinaceous network called the nuclear lamina, which underlies the nuclear membrane. EDMD can also be X-linked, in which mutations of the EMD (aka STA) gene are responsible. EMD encodes emerin, an inner nuclear membrane protein, which forms a complex with lamin A/C, cross-linking chromatin, through the nuclear lamina to the inner nuclear membrane. Mutations in LMNA and EMD are thought to result in satellite cell dysfunction. Since satellite cells are the resident stem cells responsible for repair of skeletal muscle, this dysfunction may directly contribute to EDMD.

Our long-term objective is to understand the role that lamin A/C and emerin plays in satellite cells and how their mutation causes EDMD. Satellite cells from muscles throughout the body will be examined as their heterogeneity could form the basis of different responses of muscle groups to disorders such as EDMD. Expression profiles of these nuclear proteins will be determined in wild-type quiescent satellite cells and during their activation, proliferation, self-renewal and differentiation using immunostaining. Muscle and satellite cells from lamin A/C and emerin null mice will be examined to determine how lack of these proteins affects satellite cell behaviour. Their ability to make muscle and self-renew will also be assayed in vivo using transplantation. Since ~85% of X-linked EDMD result from null mutations in EMD, these studies have direct relevance to the human disorder.

Mutant proteins in most A-EDMD and ~15% of X-EDMD patients cause a gain or change of function. How these same mutated proteins affect mouse satellite cell behaviour will be examined following viral-mediated delivery. Since human and mouse myoblasts fuse to form mosaic multi-nucleated myotubes, many signalling molecules must interact. Findings on mouse satellite cells therefore, should be broadly applicable to human, but muscle cells obtained from EDMD patients will also be examined for cell cycle and differentiation defects. Theoretically, manipulation of satellite cells could both augment and prolong muscle function in all muscular dystrophies, with the advantage of also maintaining an environment capable of responding to other therapeutic interventions. General principles of satellite cell regulation are also relevant to muscle loss in diseases such as cancer and during aging. This project falls within the musculoskeletal research priority area for PSCSB.