Duchenne muscular dystrophy is severe degenerative disease of muscle which causes death in affected boys in their mid-20s. Dystrophic muscles are more sensitive to stretch-induced muscle damage and this may be part of the damage pathway. We have recently shown that blockers of stretch-activated channels prevent Na⁺  and Ca²⁺  entry into muscles following stretch-induced damage and also reduce some of the muscle damage. In this project muscles will be removed from mdx mice (an animal model of muscular dystrophy) and the ability of drugs to reduced muscle damage will be tested.

The pacemaker region in the mouse heart contains a new discovered store-operated channel which may have a role in normal pacemaker activity.   The project aims to indentify the functional role of this channel.  The techniques involved include isolating intact sino-atrial nodes of mice and investigating function with electrophysiology, fluorescent calcium indicators and immunohistochemistry.

Stretch-induced changes in cardiac muscle are involved in the Frank-Starling relation, in arrhythmogenesis and in cardiac hypertrophy.  Very recent evidence suggests that the channels are encoded by TRPC1.  In this project single cardiac ventricular cells will be isolated and stretched with carbon fibre rods.  Using patch-clamping and confocal microscopy we will study the electrophysiological characteristics and ionic and functional consequences of the stretch-activated channels in ventricular muscle.

The mechanisms of muscle fatigue continue to be investigated.  With Terence Moopanar, we recently showed that fatigue at 37 ^oC is strongly influenced by reactive oxygen species which reduce the Ca²⁺-sensitivity of the contractile proteins.  In this project we will study the mechanism of ROS production and the target proteins of ROS-induced fatigue. 

Moopanar, T.R. & Allen, D. G. (2005).  Reactive oxygen species reduce Ca²⁺ sensitivity in fatiguing mouse skeletal muscle at 37 ^oC,  Journal of Physiology 564, 189-199.

Moopanar, T.R. & Allen, D.G. (2006).  The activity-induced reduction of Ca²⁺-sensitivity in mouse skeletal muscle is reversed by dithiothreitol Journal of Physiology 571, 191-200.

The causes of the dilated cardiomyopathy which developes as an end-stage in Duchenne muscular dystrophy.  Recent work has established that reactive oxygen species have a role in development of cardiomyopathy and that scavenging ROS delays the onset of heart disease.  In this project we hope to identify the intracellular pathways of ROS production and the mechanisms which contribute to the development of cardiomyopathy.

Williams, I. A. & Allen, D. G.  (2007).  Intracellular calcium handling in ventricular myocytes from mdx mice.  American Journal of Physiology - Heart & Circulation 292, H846-H855

Williams, I. A. & Allen, D. G.  (2007).  ROS scavengers reduce the cellular changes of dilated cardiomyopathy in mdx mouse hearts (in preparation).

Home - Research - Lab team - Publications - Contact us

Website developed and maintained by Othon Gervasio