Tier 3 — preclinical

Impact of Alpha-Ketoglutarate on Skeletal Muscle Health and Exercise Performance: A Narrative Review

Miaomiao Xu, Qiao Zhang, Xiaoguang Liu, Liming Lu, Zhaowei Li
Nutrients 2024 Volume 16, issue 22, article 3968

Bibliography

PubMed
PMID 39599754
PubMed Central
PMC11597751
DOI
10.3390/nu16223968
Funding
This work was supported by the Project of Humanities and Social Sciences (Grant No. 22YJC890014) funded by the Ministry of Education of China; the National Natural Science Foundation of China (Grant No. 32300964); the Guangdong Basic and Applied Basic Research Foundation (Grant No. 2022A1515111105) funded by the Department of Science and Technology of Guangdong Province; and the Guangzhou Basic and Applied Basic Research Foundation (Grant No. 2023A04J0552) funded by the Guangzhou Municipal Science and Technology Bureau.
Competing interests
The authors declare that they have no conflicts of interest.

Study snapshot

DesignNarrative review
ModelMuscle satellite cells (MuSCs); murine models including aged mice, mdx dystrophic mice, and LPS-challenged piglets; C2C12 myotube cell line; human trained and untrained adults and adolescent athletes
SampleNot applicable — synthesised 112 peer-reviewed articles from a 945-article initial PubMed/Web of Science/Scopus search to 31 October 2024
InterventionMultiple AKG formulations including L-arginine α-ketoglutarate (AAKG), ornithine α-ketoglutarate (OKG), sodium AKG, calcium salt of β-hydroxy-β-methylbutyrate combined with AAKG, and 5-hydroxymethylfurfural (5-HMF) plus AKG; oral, intraperitoneal, dietary, and drinking-water routes across study-specific doses
DurationNot applicable
EndpointsMuscle satellite cell proliferation and macrophage M1→M2 polarisation; Skeletal muscle protein synthesis via mTOR/S6K1/S6 pathway activation; Prevention of muscle atrophy in corticosterone, LPS, disuse, dystrophy, and lipotoxicity models; Bench press one-repetition maximum (1RM) and Wingate peak power in resistance-trained adults; Endurance and fatigue markers under normoxic and acute hypoxic conditions

What the study showed, in plain terms

This 2024 review from Guangzhou University of Chinese Medicine synthesises 112 studies on how alpha-ketoglutarate (AKG) affects skeletal muscle. It covers three questions: does AKG help muscle regenerate after injury, does it prevent muscle atrophy in ageing and disease, and does it improve exercise performance in healthy people or athletes.

The muscle-regeneration and muscle-atrophy sections lean heavily on rodent and cell-culture data. AKG appears to stimulate muscle satellite cells (the stem-cell pool that repairs muscle), shift macrophages from a pro-inflammatory to a repair phenotype, and switch on the mTOR protein-synthesis pathway. In mouse models of dystrophy, sepsis-induced wasting, and dietary lipotoxicity, AKG supplementation preserves muscle mass and function. In a Duchenne muscular dystrophy mouse model, roughly 2% AKG in drinking water improved grip strength, endurance, and hindlimb muscle weights.

The exercise-performance section is more directly relevant to healthy adults but the human evidence is thin. Small trials of L-arginine α-ketoglutarate (AAKG) show improved bench-press 1RM and Wingate anaerobic power but no change in aerobic capacity, body composition, or isokinetic endurance. Combined AKG + 5-HMF supplementation gave mixed results for exercise capacity under acute hypoxia. The review closes by acknowledging that large-scale, well-controlled human trials of AKG for muscle health and performance are still missing, and dosing regimens vary widely across the small studies that do exist.

Key findings

  • Preclinical studies reviewed link AKG with skeletal-muscle regeneration, satellite-cell biology, mitochondrial/metabolic regulation and attenuation of several atrophy pathways.
  • In mdx mouse work discussed by the review, AKG was administered at 2% in drinking water; this is not '2% of body weight' and should not be translated directly into a human dose.
  • Human exercise-performance studies in the review are limited and often small; several use arginine alpha-ketoglutarate (AAKG) or combination formulations rather than Ca-AKG.
  • Across the review, proposed mechanisms include effects on energy metabolism, AMPK/mTOR-related signaling, oxidative stress, inflammatory pathways and epigenetic enzymes.
  • The literature is heterogeneous across species, formulations, doses, training status and endpoints, preventing a single pooled estimate of efficacy.

What this study can and cannot tell us

The authors used a structured multi-database search and study-quality screening, but the paper is a narrative synthesis and does not provide a quantitative meta-analysis. Species, formulations, doses, durations and endpoints are highly heterogeneous.

Most evidence for muscle regeneration and anti-atrophy mechanisms is preclinical. Cell and animal results should not be treated as proof of clinically meaningful muscle benefit in humans.

Human performance studies are generally small and frequently use AAKG or multi-ingredient products. Those findings cannot be attributed to AKG alone or transferred directly to calcium-AKG.

The review therefore supports biological plausibility and hypothesis generation more strongly than it supports a defined oral Ca-AKG dose, magnitude of effect or clinical indication.

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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