Tier 3 — preclinical

Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation

Yuan Y, Xu P, Jiang Q, Cai X, Wang T, Peng W, Sun J, Zhu C, Zhang C, Yue D, He Z, Yang J, Zeng Y, Du M, Zhang F, Ibrahimi L, Schaul S, Jiang Y, Wang J, Sun J, Wang Q, Liu L, Wang S, Wang L, Zhu X, Gao P, Xi Q, Yin C, Li F, Xu G, Zhang Y, Shu G
The EMBO Journal 2020 39(7):e103304

Bibliography

PubMed
PMID 32104923
PubMed Central
PMC7110140
DOI
10.15252/embj.2019103304
Funding
Supported by the National Key Point Research and Invention Program (2018YFD0500403; 2016YFD0501205), National Natural Science Foundation of China (31790411; 31572480), Research and Development Projects in Key Areas of Guangdong Province (2019B020218001), Innovation Team Project in Universities of Guangdong Province (2017KCXTD002), and NIH/NIDDK grants R00DK107008 and K01DK111771.
Competing interests
The authors declared no conflict of interest.

Study snapshot

DesignTranslational mouse intervention and human observational study.
ModelMouse exercise and pharmacologic AKG models plus human plasma observations.
SampleMultiple mouse cohorts; human plasma analysis included 45 adults.
InterventionPharmacologic elevation of circulating AKG in mice; no human supplementation arm.
DurationStudy-specific exercise and intervention protocols.
EndpointsMuscle hypertrophy; Brown adipose thermogenesis; White adipose lipolysis; Adrenaline release; OXGR1 signaling; Human plasma AKG and BMI

What the study showed, in plain terms

This EMBO Journal study identified AKG as an exercise-responsive metabolite and mapped a receptor-mediated pathway connecting it to muscle and fat biology.

In mice, raising circulating AKG promoted muscle hypertrophy, brown-fat thermogenesis and white-fat lipolysis through adrenal OXGR1-dependent adrenaline release. In a small human observational component, plasma AKG was negatively correlated with BMI.

The human data are correlational; the intervention evidence is in mice and does not show that an oral Ca-AKG supplement causes fat loss or muscle gain in people.

Key findings

  • Resistance exercise increased circulating AKG in experimental models.
  • Pharmacologic AKG elevation triggered OXGR1-dependent adrenal activation in mice.
  • Mouse AKG exposure increased muscle hypertrophy and fat mobilization; human plasma AKG correlated inversely with BMI.

What this study can and cannot tell us

  • Human component was observational only; the intervention evidence was in mice.
  • Mouse pharmacologic AKG exposure is not equivalent to retail Ca-AKG dosing.
  • A 2021 published corrigendum corrected images in Appendix Figure S3D, changed one text reference from endurance exercise to resistance exercise, and clarified a figure legend. The authors stated that these corrections did not affect the conclusions or statistics.

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Dr. Khaled Mahmoud, MBBChCritical Care Medicine, Longevity Science & Editorial Direction Dr. Amr Yasser, PhDCardiometabolic, Musculoskeletal, Gut & Bioavailability Dr. Abdulla Mostafa, PhDCellular Senescence, Neurological, Mitochondrial & Brain-Ageing Biology