Intramuscular Inflammation, Exercise and Muscle Wasting in Chronic Kidney Disease

Chronic kidney disease (CKD) patients suffer from skeletal muscle wasting. This is a debilitating complication that has a significant impact on morbidity, mortality and quality of life. Despite these severe consequences, our understanding of why CKD patients lose muscle mass is incomplete, hindering preventative measures. Therefore, mechanistic research is of paramount importance to develop effective preventative interventions.In the thesis, low muscle mass was demonstrated in non-dialysis CKD patients (Chapter 4). This was associated with reduced physical function and was concurrent with systemic and intramuscular inflammation, potentially representing a mechanism for muscle loss in CKD. Within this field, there is a reliance on immortalised cell lines which lack translation to human physiology. To address this limitation, a cell culture model of human primary skeletal muscle cells derived from biopsies collected from CKD patients was characterised (Chapter 5) and used to demonstrate that CKD derived myoblasts and myotubes do not retain in vivo characteristics of muscle wasting and dysfunction. Alternatively, recreation of the in vivo systemic environment by culturing human derived cells in serum from CKD patients increased myoblast proliferation and decreased myotube diameter (Chapter 6). There was also evidence of reduced Akt phosphorylation in response to CKD derived serum (Chapter 7). However similar, but less pronounced, effects were also seen in response to serum derived from healthy controls. Therefore, further work is required to delineate the effect of the systemic CKD environment on human skeletal muscle cells in vitro.The work presented in this thesis is the first example of the use of human primary skeletal muscle cells in renal research, thereby providing a novel contribution to the literature. Further development of this model and research studying the effect of the systemic and intramuscular uraemic environment on human derived skeletal muscle cells will expand our understanding of why CKD patients experience muscle loss, highlighting avenues for potential therapies.