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

Daniel C Bittel, Adam J Bittel, Arun S Varadhachary, Terri Pietka, David R Sinacore

Diabetes 2021 May

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Two-thirds of people with type 2 diabetes mellitus (T2DM) have or will develop chronic kidney disease (CKD), which is characterized by rapid renal decline that, together with superimposed T2DM-related metabolic sequelae, synergistically promotes early frailty and mobility deficits that increase the risk of mortality. Distinguishing the mechanisms linking renal decline to mobility deficits in CKD progression and/or increasing severity in T2DM is instrumental both in 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-generation 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 relate 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. © 2021 by the American Diabetes Association.

Citation

Daniel C Bittel, Adam J Bittel, Arun S Varadhachary, Terri Pietka, David R Sinacore. Deficits in the Skeletal Muscle Transcriptome and Mitochondrial Coupling in Progressive Diabetes-Induced CKD Relate to Functional Decline. Diabetes. 2021 May;70(5):1130-1144