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Research article - Peer-reviewed, 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

Sjogren, Rasmus J. O.; Rizo-Roca, David; Chibalin, Alexander, V; Chorell, Elin; Furrer, Regula; Katayama, Shintaro; Harada, Jun; Karlsson, Hakan K. R.; Handschin, Christoph; Moritz, Thomas; Krook, Anna; Naslund, Erik; Zierath, Juleen R.;

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.

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

Published in

Diabetologia

2021, volume: 64, number: 9, pages: 2077-2091
Publisher: SPRINGER

Authors' information

Sjogren, Rasmus J. O.
Karolinska Institutet
Rizo-Roca, David
Karolinska Institutet
Chibalin, Alexander
Karolinska Institutet
Chorell, Elin
Umea University
Furrer, Regula
University of Basel
Katayama, Shintaro
Karolinska Institutet
Harada, Jun
Daiichi Sankyo Company Limited
Karlsson, Hakan K. R.
Karolinska Institutet
Handschin, Christoph
University of Basel
Krook, Anna
Karolinska Institutet
Naslund, Erik
Karolinska Institutet
Zierath, Juleen R.
Karolinska Institutet
Swedish University of Agricultural Sciences, Department of Forest Genetics and Plant Physiology

Sustainable Development Goals

SDG3 Good health and wellbeing

UKÄ Subject classification

Endocrinology and Diabetes

Publication Identifiers

DOI: https://doi.org/10.1007/s00125-021-05481-9

URI (permanent link to this page)

https://res.slu.se/id/publ/112695