Deficits in the Skeletal Muscle Transcriptome and Mitochondrial Coupling in Progressive Diabetes-Induced CKD Relate to Functional Decline

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posted on 01.02.2021, 22:34 by Daniel C. Bittel, Adam J. Bittel, Arun S. Varadhachary, Terri Pietka, David R. Sinacore
Two-thirds of those with type-2 diabetes (T2DM) have or will develop chronic kidney disease (CKD), characterized by rapid renal decline that, together with superimposed T2DM-related metabolic sequelae, synergistically promote early frailty and mobility-deficits that increases risk of mortality. Distinguishing the mechanisms linking renal decline to mobility deficits in CKD progression and/or increasing severity in T2DM is instrumental in both identifying those at high-risk for functional decline, and in formulating effective treatment strategies to prevent renal failure. While evidence suggests that skeletal muscle energetics may relate to the development of these comorbidities in advanced-CKD, this has never been assessed across the spectrum of CKD progression, especially in T2DM-induced CKD. Here, using next-gen sequencing, we first report significant downregulation in transcriptional networks governing oxidative phosphorylation, coupled electron-transport, electron-transport-chain(ETC)-complex assembly, and mitochondrial organization in both middle- and late-stage CKD in T2DM. Furthermore, muscle mitochondrial coupling is impaired as early as stage 3-CKD, with additional deficits in ETC-respiration, enzymatic activity, and increased redox-leak. Moreover, mitochondrial ETC function and coupling strongly related to muscle performance, and physical function. Our results indicate that T2DM-induced CKD progression impairs physical function, with implications for altered metabolic transcriptional networks and mitochondrial functional deficits, as primary mechanistic factors early in CKD-progression in T2DM.


This work was supported in part by National Institutes of Health (NIH) grants 5T32HD007434-26 (Dr. Catherine Lang), 1F31DK109649-01A1 (DCB), UL1 TR002345 (DCB and DRS). This work was also supported by the American Physical Therapy Association (APTA) Foundation for Physical Therapy Research (PODS awards: 2015-2017, to DCB).