SEMINAR: Lipid replacement of myofibres in dysferlin-deficient muscles

The Seminar: There many forms of muscular dystrophy that affect skeletal muscles; some manifest in children e.g. Duchenne Muscular Dystrophy (DMD), whereas the onset for others is after adolescence e.g. dyferlinopathies, or in older adults. Thus age and growth influence the onset and severity of different dystrophies. The first part of this seminar will discuss the consequences of growth on the long multinucleated contractile skeletal muscle cells (myofibres) and implications for manifestation of DMD and dysferlinopathies. The second part of the talk will present new data related to understanding the mechanisms that lead to the pathology of dysferlinopathy. Dysferlin is a membrane associated protein involved in protein vesicle trafficking and fusion, with genetic defects leading to dysferlinopathies that are evident in males and females soon after the cessation of growth. Dysferlinopathies include the human Limb Girdle Muscular Dystrophy type 2B and Miyoshi Myopathy, plus animal models such as dysferlin-deficient A/J mice. The precise basis for the disease pathology is not understood: to date much research has focussed on issues of membrane resealing and stem cells as well as the role of inflammatory cells. We have recently demonstrated striking lipid accumulation that replaces myofibres in muscles of dysferlin-deficient mice, without conspicuous myofibre necrosis (Terrill J et al, 2013). Our recent data will be presented from studies using a range of techniques including electron microscopy and Oil red O staining to investigate the high lipid content of mature dysferlin-deficient muscles of humans and mice. These novel observations implicate major metabolic disturbances within mature dysferlin-deficient muscles that may be central to the pathological features of dysferlinopathies.

The Speaker: Miranda Grounds graduated from the University of Western Australia (UWA) with a Bachelor of Science (Biochemistry) with Honours in 1969, gained a PhD from the University of London in 1978, returned to UWA to become an independent researcher funded by the National Health & Medical Research Council of Australia (in Pathology) in 1980 and was appointed in 1994 as Professor in the School of Anatomy, Physiology and Human Biology. For over 35 years, her research has focussed on in vivo cell and molecular studies of skeletal muscle using various mouse models of normal, diseased and ageing muscles: this involves two broad areas of research interest. One investigates the factors controlling the damage, repair and maintenance of normal skeletal muscle, including tissue engineering and age-related loss of skeletal muscle mass and function. The second approach applies these findings to understanding the molecular basis for a wide range of muscle disorders, and developing potential treatments for Duchenne muscular dystrophy (DMD) and dysferlinopathies. MG is involved in various international muscle agencies and parent groups related to these muscular dystrophies, along with the Treat-NMD network with membership of the clinical trial evaluation committee (TACT). This research is widely recognised internationally and has generated about 170 publications: http://school.anhb.uwa.edu.au/personalpages/grounds/