Functional and Skeletal Muscle Impairments In Progressive Diabetic CKD
Date of Award
Doctor of Philosophy (PhD)
Chair and Committee
David R. Sinacore
David R. Sinacore, Arun Varadhachary, Gretchen Meyer, Todd Cade
1-in-3 persons with type 2 diabetes (T2DM) develop chronic kidney disease (CKD), which is characterized by progressive renal dysfunction leading to end-stage renal disease. In response to elevated blood glucose and systemic inflammation of diabetes, a process of active thickening of the renal glomerular basement membrane ensues with concomitant damage to the structural supports (podocytes) of the kidneyճ filtration barrier. This results in impaired renal filtration. The metabolic sequelea of T2DM and CKD also, synergistically, alter skeletal muscleճ degradative pathways, satellite cell function (muscle reparative cells), and mitochondrial health (muscle energetic machinery) -- resulting in muscle breakdown, poor muscle quality, and exercise intolerance, and immobility that exacerbates CKD. The temporal nature and extent of these changes in CKD, however, remains unknown. With mandates from the Center for Disease Control (CDC) urging avenues of treatment that impede the progression of CKD, it is critical now, more than ever, to gain a better understanding of the factors that contribute to disease progression. This will inform more effective targeted interventions. We therefore aim to determine how renal dysfunction dictates the activity of muscle degredative pathways, the status of muscle reparative cells, and the energetic production of muscle, to ultimately influence muscle quality, performance and physical mobility. This will be determined across stages of CKD.
In chapter 1, we examine how CKD progression in T2DM, impacts muscle performance and physical function. Our results suggest that muscle performance of the lower extremity, particularly the quadriceps, and physical function decline in-parallel with progression of CKD in T2DM, with these declines becoming clinically evident in stage 3. Moreover, we find that CKD-stage, and renal filtration/function (eGFR) are both significant predictors of overall physical function, with increasing CKD stage/worsening kidney filtration predicting worse functional mobility. In chapter 2, we examine the CKD-stage specific functional status of skeletal muscle mitochondrial ATP production, and electron transport chain kinetics, as these are critical cellular processes to fuel muscle cross-bridge cycling, contraction and movement. We find that intrinsic skeletal muscle mitochondrial electron transport chain function is reduced with progression of CKD, with significant reductions in ATP-production capacity emerging as early as stage 3 CKD. Moreover, these changes may derive from transcriptome-level alterations in gene networks governing muscle mitochondrial health and function. In Chapter 3, we examine muscle regenerative and maintenance capacity in relationship to CKD progression. We find the muscle-resident satellite cell pool to decline significantly with CKD progression, and exhibit impaired myogenic capacity with altered gene activation patterns, that relate strongly to findings of poor muscle quality with progressive CKD stage. Using transcriptomics, we report significant dowregulation in gene networks that influence muscle SC behavior and myogenesis.
Overall, our data suggests that the progression of diabetes-induced chronic kidney disease, is paralleled by impairments in skeletal muscle ATP-producing capacity, and these energetic deficits are accompanied by CKD-associated reductions in muscle SC abundance, and reparative function. Both changes perhaps stem from alterations in gene pathway expression that is imparted by the altered uremic environment. These impairments may promote the development of poor muscle quality and performance that ultimately impairs functional capacity, even in middle-stage CKD.
Bittel, Daniel, "Functional and Skeletal Muscle Impairments In Progressive Diabetic CKD" (2018). WUSM Theses and Dissertations – All Programs. 13.