Investigation of Pre-Pathological Aetiology of Dysferlinopathy in the mouse

Terence Partridge, PhD

Children's National Medical Center (Washington, DC)

Dr. Partridge is a Principal Investigator in the Children's Research Institute Center for Genetic Medicine Research (CGMR) and a Professor of Pediatrics at the George Washington University School of Medicine and Health Sciences (Washington, DC).

Past Projects

Objective: 
Tracing the changes that accompany onset of disease in dysferlin-deficient muscle

We are interested in one of the main mysteries of dysferlin deficiency; how individuals who lack dysferlin appear to have perfectly normal muscle function for much of the early part of their lives but go on to have increasingly severe loss of muscle later in life.  This change is seen in the mouse models of dysferlin deficiency, too. Young BlaJ mice show no sign of spontaneous muscle pathology, but after the end of growth at about 4 months there are signs of degeneration and regeneration. We have taken the tack that this is likely to be associated with changes in protein composition and in production of cytokines that act as signals to regulate the processes of muscle maintenance.  We are using modern proteomic techniques to compare the protein composition of muscles from normal control mice and dysferlin-deficient animals over a range of ages, covering the stage at which the muscles appear normal to the stage when the pathology is severe.  The pattern of cytokine production over this period is also being assessed.

In combination with this, we are monitoring the size of the individual muscle fibres in terms of the number of nuclei in each fibre, a sign of how big a part regeneration from satellite cells is playing, and also in terms of the amount of contractile protein present, a sign of how active the nuclei are in maintaining protein balance.

From these data, we expect to build up picture of the onset of disease arising from dysferlin deficiency. In particular, we hope to pick up the early signs of aberrant protein metabolism and of the changes in inter- and intra-cellular signaling involved in the change from apparently normal to diseased muscle function.  Analysis of such associations will inform us of the molecular and cellular mechanisms implicated in the disease process as causative features or as results of the pathology. Together, they will help build a detailed picture of what pathological processes may be therapeutic targets.