Mersey Kidney First

Role of defective mitochondrial function in skeletal muscle weakness in patients with chronic kidney disease

Prof A McArdle, Dr A V Crowe, Dr A Sharma, Dr A Kayani

Advanced chronic kidney disease (CKD) is a severe and debilitating disease suffered by a growing number of people worldwide. The impact on the lives of sufferers is profound, with most experiencing significant reduction in their quality of life. We believe that skeletal muscle atrophy/weakness and a reduced ability to exercise is a significant factor, concomitant with the underlying renal disease. It is believed that a change in the normal function of mitochondria (the powerhouse of the cell) in the muscle of CKD patients contributes to muscle loss and weakness. Mitochondria provide the source of energy (ATP) for muscle to contract and are involved in a process termed redox signalling through production of reactive oxygen species (ROS). ROS are produced during normal respiration; however, accumulation of ROS leads to oxidative damage of muscle. Furthermore, ROS induces the activation of a molecule termed nuclear factor kappa B (NFkB) which causes the release of harmful substances (pro-inflammatory cytokines) which contribute to the wasting or atrophy of skeletal muscle. Skeletal muscle dysfunction in CKD patients prior to haemodialysis is poorly understood. Therefore, more research is necessary to determine the precise mechanisms underlying loss of skeletal muscle and weakness in patients with CKD. We aim to characterise muscle weakness and perturbations in mitochondrial function in fibres from healthy volunteers and CKD patients aged 40-60 years. In addition we aim to identify changes in ROS and NFkB in these individuals. This initial study will provide a firm basis for the development of an intervention study to address skeletal muscle dysfunction in patients with CKD. We believe that obtaining a greater understanding of mitochondria associated muscle weakness will allow for future development of pharmacological or physiological interventions to improve quality of life for patients with CKD.

The research project is progressing well. Our laboratory has developed, refined and validated the techniques used in the analysis of the muscle biopsies. Muscle biopsy analyses are underway and the research team has successfully performed biopsies from a number of healthy volunteers. The biopsies have been processed, analysed and data gathered. We have expanded our healthy volunteer recruitment to encompass the whole of the Merseyside area, by engagement through the local press and media. The main focus of the research teams is currently centred on recruitment of CKD patients at the Aintree and Arrowe Park sites which has also now begun.

Research Partners
Liverpool University The Royal Liverpool and Broadgreen University Hospital
Supported by
Mitchell Charlesworth