Characterization and novel imaging of skeletal muscle fibrosis in patients with chronic kidney disease

Mobility impairment and disability are common in people with advanced chronic kidney disease (CKD) and are major contributors to morbidity and mortality. An improved understanding of contributing factors is needed to guide effective interventions. Skeletal muscle fibrosis has received little attention despite being ubiquitously present in animal models of muscle atrophy including CKD. Proper maintenance of the extracellular matrix (ECM) requires coordinated interactions of several cell types, including satellite cells (muscle stem-like cells) and several fibrogenic precursor cell types. These cells are highly sensitive to the extracellular milieu, and in uremic animals muscle fibrosis occurs due to impaired satellite cell function. As excess ECM deposition and fibrosis reduce muscle specific force, and as fibrosis is often accompanied by myofiber atrophy and capillary rarefaction, muscle fibrosis may be an important contributor to mobility impairment in CKD. The focus of this application is the characterization of skeletal muscle fibrosis in an ongoing study of patients with advanced CKD and the development of non- invasive imaging methods to quantify fibrotic burden that can be widely applied to populations at risk. We will (1) determine whether skeletal muscle fibrosis is increased in humans with CKD and characterize satellite cell and fibrogenic precursor cell abundance and TGF-? signaling in quadriceps muscle biopsies; (2) determine if MRI-based measures of muscle fibrosis are increased in humans with CKD and represent a novel non-invasive means of quantifying fibrotic burden; and (3) explore the association of skeletal muscle fibrosis with muscle strength and physical function in patients with CKD. Thus, these studies will provide new insights into human skeletal muscle pathology and will facilitate its further study with novel non-invasive means of assessment.