Muscle loss and declining muscle strength are prominent physiological changes during aging, which directly affect exercise capacity and quality of life in the elderly. As a key intermediate metabolite of the tricarboxylic acid cycle, alpha-ketoglutarate (AKG) has drawn growing attention in anti-aging research.
Accumulating animal and human studies suggest it is tightly linked to skeletal muscle metabolism. This narrative review focuses on the impact of alpha-ketoglutarate on skeletal muscle health and exercise performance, sorting out available evidence, underlying mechanisms and existing research limitations. Below is the core content from the review abstract:
AKG, a central metabolite in the Krebs cycle, plays a vital role in cellular energy production and nitrogen metabolism. This review explores AKG's potential therapeutic applications in skeletal muscle health and exercise performance, focusing on its mechanisms for promoting muscle regeneration and counteracting muscle atrophy.
Figure 1. Metabolic role of AKG in the TCA cycle and nitrogen metabolism. This figure illustrates AKG's role within the TCA cycle, in which it facilitates the conversion of isocitrate to succinyl-CoA, generating NADH for ATP synthesis. AKG also participates in nitrogen metabolism through transamination, producing glutamate, which serves as a precursor for amino acids like GABA, GSH, and essential amino acids, such as aspartate, glutamine, leucine, and proline. These pathways underscore AKG's contribution to cellular energy production, amino acid synthesis, and nitrogen balance. TCA, tricarboxylic acid; AKG, alpha-ketoglutarate; NADH, nicotinamide adenine dinucleotide; GSH, glutathione; GABA, gamma-aminobutyric acid.
A literature search was conducted using the PubMed, Web of Science, and Scopus databases, yielding 945 articles published up to 31 October 2024. Of these, 112 peer-reviewed articles met the inclusion criteria and formed the basis of this review.
AKG supports muscle recovery by stimulating muscle satellite cells (MuSCs) and macrophage polarization, aiding muscle repair and reducing fibrosis. Additionally, AKG shows promise in preventing muscle atrophy by enhancing protein synthesis, inhibiting degradation pathways, and modulating inflammatory responses, making it relevant in conditions like sarcopenia, cachexia, and injury recovery. For athletes and active individuals, AKG supplementation has enhanced endurance, reduced fatigue, and supported faster post-exercise recovery.
Despite promising preliminary findings, research gaps remain in understanding AKG's long-term effects, optimal dosage, and specific pathways, particularly across diverse populations. Further research, including large-scale clinical trials, is essential to clarify AKG's role in muscle health and to optimize its application as a therapeutic agent for skeletal muscle diseases and an enhancer of physical performance.
This review aims to provide a comprehensive overview of AKG's benefits and identify future directions for research in both clinical and sports settings.
