PMID- 33526590
OWN - NLM
STAT- MEDLINE
DCOM- 20210824
LR  - 20220503
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 70
IP  - 5
DP  - 2021 May
TI  - Deficits in the Skeletal Muscle Transcriptome and Mitochondrial Coupling in 
      Progressive Diabetes-Induced CKD Relate to Functional Decline.
PG  - 1130-1144
LID - 10.2337/db20-0688 [doi]
AB  - 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.
CI  - (c) 2021 by the American Diabetes Association.
FAU - Bittel, Daniel C
AU  - Bittel DC
AUID- ORCID: 0000-0001-7951-1900
AD  - Program in Physical Therapy, Washington University School of Medicine, St. Louis, 
      MO dcbittel@wustl.edu.
FAU - Bittel, Adam J
AU  - Bittel AJ
AD  - Program in Physical Therapy, Washington University School of Medicine, St. Louis, 
      MO.
FAU - Varadhachary, Arun S
AU  - Varadhachary AS
AD  - Department of Neurology, Washington University School of Medicine, St. Louis, MO.
FAU - Pietka, Terri
AU  - Pietka T
AD  - Center for Human Nutrition, Washington University School of Medicine, St. Louis, 
      MO.
FAU - Sinacore, David R
AU  - Sinacore DR
AD  - Program in Physical Therapy, Washington University School of Medicine, St. Louis, 
      MO.
AD  - Department of Physical Therapy, Congdon School of Health Sciences, High Point 
      University, High Point, NC.
LA  - eng
SI  - figshare/10.2337/figshare.13643477
GR  - F31 DK109649/DK/NIDDK NIH HHS/United States
GR  - T32 HD007434/HD/NICHD NIH HHS/United States
GR  - UL1 TR002345/TR/NCATS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20210201
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Electron Transport Chain Complex Proteins)
SB  - IM
MH  - Animals
MH  - Diabetes Mellitus, Type 2/*metabolism/pathology
MH  - Electron Transport Chain Complex Proteins/genetics/*metabolism
MH  - Humans
MH  - Mitochondria/*metabolism
MH  - Muscle, Skeletal/*metabolism
MH  - Renal Insufficiency, Chronic/*metabolism/pathology
MH  - Transcriptome/*genetics
PMC - PMC8173802
EDAT- 2021/02/03 06:00
MHDA- 2021/08/25 06:00
PMCR- 2022/05/01
CRDT- 2021/02/02 06:02
PHST- 2020/07/02 00:00 [received]
PHST- 2021/01/25 00:00 [accepted]
PHST- 2021/02/03 06:00 [pubmed]
PHST- 2021/08/25 06:00 [medline]
PHST- 2021/02/02 06:02 [entrez]
PHST- 2022/05/01 00:00 [pmc-release]
AID - db20-0688 [pii]
AID - 200688 [pii]
AID - 10.2337/db20-0688 [doi]
PST - ppublish
SO  - Diabetes. 2021 May;70(5):1130-1144. doi: 10.2337/db20-0688. Epub 2021 Feb 1.