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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

DOI: 10.3390/nu16223968
PubMed: PMID 39599754
PubMed Central: PMC11597751
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

Design	Narrative review
Model	Muscle 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
Sample	Not applicable — synthesised 112 peer-reviewed articles from a 945-article initial PubMed/Web of Science/Scopus search to 31 October 2024
Intervention	Multiple 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
Duration	Not applicable
Endpoints	Muscle 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

AKG levels fall in ageing mouse myoblasts. Primary myoblasts from aged mice have significantly lower AKG than adult-mouse cells; AKG supplementation restores myoblast proliferation (Ciuffoli 2024).
Post-injury regeneration in aged mice. Intraperitoneal AKG before injury and on days 1, 3, and 5 post-injury significantly increased satellite-cell number and regenerating fibre cross-sectional area, and reduced fibrosis at 28 days post-cardiotoxin injury.
PHD3/ADRB2 pathway in dystrophy. AKG at 2% body weight in drinking water improved limb muscle strength, endurance, body weight, gastrocnemius weight, and soleus weight in mdx mice; the mechanism involves inhibition of PHD3 and stabilisation of the β2-adrenergic receptor (Cai 2018).
mTOR activation in piglets. Dietary AKG in LPS-challenged and low-protein-diet piglets activated mTOR signalling, normalised plasma TNF-α and IGF-1, and improved skeletal muscle energy status.
OKG post-cholecystectomy. Adding ornithine-α-ketoglutarate to total parenteral nutrition after gallbladder surgery preserved skeletal muscle protein synthesis (stable ribosome concentration and polyribosome percentage) and reduced urinary urea excretion (Wernerman 1987).
AAKG improves 1RM and Wingate power. In 35 resistance-trained men, 12 g/day AAKG for 8 weeks significantly improved bench-press 1RM and Wingate peak power versus placebo, with no change in body composition, isokinetic quadriceps endurance, or aerobic capacity, and no adverse changes in clinical blood markers (Campbell 2006).
Untrained adults, 4 weeks. 0.2 g/kg/day AKG in untrained men increased training volume, maximum power output, and muscle torque, and improved stress-recovery state (Liu 2012).
Hypoxia results are mixed. Three weeks of 2.4 g/day AKG + 90 mg/day 5-HMF prevented aerobic-performance decline under acute normobaric hypoxia (Mariacher 2014); a shorter 2-day protocol at higher AKG dose did not (Gatterer 2013).
Anti-fatigue in young athletes. Co-supplementation of calcium β-hydroxy-β-methylbutyrate and AAKG for 12 days prevented countermovement jump decline in 14–17-year-old track and field athletes, without changes in muscle-damage markers.

What this study can and cannot tell us

Narrative, not systematic. The review does not report a PRISMA flow diagram, does not perform risk-of-bias assessment on individual included studies, and does not synthesise effect sizes quantitatively. Study weighting reflects the authors' framing.

The muscle-regeneration and atrophy evidence is almost entirely preclinical. The mechanistic sections lean on rodent, piglet, and C2C12 cell-line studies. Direct translation to human sarcopenia, cachexia, or injury recovery is not supported by the review's own evidence base — this is acknowledged in the paper's conclusion.

Human exercise-performance trials are small and heterogeneous. The largest trial in the exercise section (Campbell 2006) enrolled 35 men. Interventions include AAKG, plain AKG, AKG + 5-HMF, and AKG + calcium β-hydroxy-β-methylbutyrate at doses ranging from ~2 g/day to 12 g/day for durations of 2 days to 8 weeks — findings are not directly comparable and the review does not attempt a dose-response synthesis.

Formulation confounding. Many of the human-performance findings are for L-arginine α-ketoglutarate (AAKG), not calcium α-ketoglutarate. Arginine has independent vasodilatory and metabolic effects, so attributing AAKG performance signals to the AKG moiety alone is not supported by the reviewed studies.

Delayed-release Ca-AKG (Rejuvant) is not addressed. The review does not cover the branded delayed-release calcium-AKG formulation that dominates the current longevity-supplement market; readers of the Ca-AKG cluster should not extend the muscle findings to that specific product without further evidence.

The reviewed evidence does not include Ca-AKG randomised trials for muscle endpoints in ageing adults. ABLE (NCT05706389) and the Chinese Ca-AKG RCT (NCT07114536) had not reported when this review was published; those results will materially update the muscle and frailty evidence base once available.