Home About Browse Search
Svenska


Branched-chain amino acid metabolism is regulated by ERR alpha in primary human myotubes and is further impaired by glucose loading in type 2 diabetes

Sjogren, Rasmus J. O. and Rizo-Roca, David and Chibalin, Alexander and Chorell, Elin and Furrer, Regula and Katayama, Shintaro and Harada, Jun and Karlsson, Hakan K. R. and Handschin, Christoph and Moritz, Thomas and Krook, Anna and Naslund, Erik and Zierath, Juleen R. (2021). Branched-chain amino acid metabolism is regulated by ERR alpha in primary human myotubes and is further impaired by glucose loading in type 2 diabetes. Diabetologia. 64 , 2077-2091
[Research article]

[img] PDF
4MB

Abstract

Aims/hypothesis Increased levels of branched-chain amino acids (BCAAs) are associated with type 2 diabetes pathogenesis. However, most metabolomic studies are limited to an analysis of plasma metabolites under fasting conditions, rather than the dynamic shift in response to a metabolic challenge. Moreover, metabolomic profiles of peripheral tissues involved in glucose homeostasis are scarce and the transcriptomic regulation of genes involved in BCAA catabolismis partially unknown. This study aimed to identify differences in circulating and skeletal muscle BCAA levels in response to an OGTT in individuals with normal glucose tolerance (NGT) or type 2 diabetes. Additionally, transcription factors involved in the regulation of the BCAA gene set were identified.Methods Plasma and vastus lateralis muscle biopsies were obtained from individuals with NGT or type 2 diabetes before and after an OGTT. Plasma and quadricepsmuscles were harvested fromskeletalmuscle-specific Ppargc1a knockout and transgenic mice. BCAA-related metabolites and genes were assessed by LC-MS/MS and quantitative RT-PCR, respectively. Small interfering RNA and adenovirus-mediated overexpression techniques were used in primary human skeletal muscle cells to study the role of PPARGC1A and ESRRA in the expression of the BCAA gene set. Radiolabelled leucine was used to analyse the impact of oestrogen-related receptor alpha (ERR alpha) knockdown on leucine oxidation.Results Impairments in BCAA catabolism in people with type 2 diabetes under fasting conditions were exacerbated after a glucose load. Branched-chain keto acids were reduced 37-56% after an OGTT in the NGT group, whereas no changes were detected in individuals with type 2 diabetes. These changes were concomitant with a stronger correlation with glucose homeostasis biomarkers and downregulated expression of branched-chain amino acid transaminase 2, branched-chain keto acid dehydrogenase complex subunits and 69% of downstream BCAA-related genes in skeletal muscle. In primary human myotubes overexpressing peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha, encoded by PPARGC1A), 61% of the analysed BCAA genes were upregulated, while 67% were downregulated in the quadriceps of skeletalmuscle-specific Ppargc1a knockout mice. ESRRA (encoding ERR alpha) silencing completely abrogated the PGC-1 alpha-induced upregulation of BCAA-related genes in primary human myotubes.Conclusions/interpretation Metabolic inflexibility in type 2 diabetes impacts BCAA homeostasis and attenuates the decrease in circulating and skeletal muscle BCAA-related metabolites after a glucose challenge. Transcriptional regulation of BCAA genes in primary human myotubes via PGC-1 alpha is ERR alpha-dependent.

Authors/Creators:Sjogren, Rasmus J. O. and Rizo-Roca, David and Chibalin, Alexander and Chorell, Elin and Furrer, Regula and Katayama, Shintaro and Harada, Jun and Karlsson, Hakan K. R. and Handschin, Christoph and Moritz, Thomas and Krook, Anna and Naslund, Erik and Zierath, Juleen R.
Title:Branched-chain amino acid metabolism is regulated by ERR alpha in primary human myotubes and is further impaired by glucose loading in type 2 diabetes
Series Name/Journal:Diabetologia
Year of publishing :2021
Volume:64
Page range:2077-2091
Number of Pages:15
Publisher:SPRINGER
ISSN:0012-186X
Language:English
Publication Type:Research article
Article category:Scientific peer reviewed
Version:Published version
Copyright:Creative Commons: Attribution 4.0
Full Text Status:Public
Subjects:(A) Swedish standard research categories 2011 > 3 Medical and Health Sciences > 302 Clinical Medicine > Endocrinology and Diabetes
Keywords:Branched-chain amino acid, Oestrogen-related receptor alpha, Oral glucose tolerance test, Peroxisome proliferator-activated receptor, coactivator 1-alpha, Skeletal muscle, Type 2 diabetes
URN:NBN:urn:nbn:se:slu:epsilon-p-112695
Permanent URL:
http://urn.kb.se/resolve?urn=urn:nbn:se:slu:epsilon-p-112695
Additional ID:
Type of IDID
DOI10.1007/s00125-021-05481-9
Web of Science (WoS)000661758500002
ID Code:25022
Faculty:S - Faculty of Forest Sciences
Department:(S) > Dept. of Forest Genetics and Plant Physiology
Deposited By: SLUpub Connector
Deposited On:25 Aug 2021 13:25
Metadata Last Modified:25 Aug 2021 13:31

Repository Staff Only: item control page

Downloads

Downloads per year (since September 2012)

View more statistics

Downloads
Hits