α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway
Open accessAbstract
Skeletal muscle atrophy due to excessive protein degradation is the main cause for muscle dysfunction, fatigue, and weakening of athletic ability. Endurance exercise is effective to attenuate muscle atrophy, but the underlying mechanism has not been fully investigated. a‐Ketoglutarate (AKG) is a key intermediate of tricarboxylic acid cycle, which is generated during endurance exercise. Here, we demonstrated that AKG effectively attenuated corticosterone‐induced protein degradation and rescued the muscle atrophy and dysfunction in a Duchenne muscular dystrophy mouse model. Interestingly, AKG also inhibited the expression of proline hydroxylase 3 (PHD3), one of the important oxidoreductases expressed under hypoxic conditions. Subsequently, we identified the ß 2 adrenergic receptor (ADRB2) as a downstream target for PHD3. We found AKG inhibited PHD3/ADRB2 interaction and therefore increased the stability of ADRB2. In addition, combining pharmacologic and genetic approaches, we showed that AKG rescues skeletal muscle atrophy and protein degradation through a PHD3/ADRB2 mediated mechanism. Taken together, these data reveal a mechanism for inhibitory effects of AKG on muscle atrophy and protein degradation. These findings not only provide a molecular basis for the potential use of exercise‐generated metabolite AKG in muscle atrophy treatment, but also identify PHD3 as a potential target for the development of therapies for muscle wasting.—Cai, X., Yuan, Y., Liao, Z., Xing, K., Zhu, C., Xu, Y., Yu, L., Wang L., Wang S., Zhu, X., Gao P. Zhang Y. Jiang Q. Xu P. Shu G. α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway. FASEB J. 32,488‐499 (2018). www.fasebj.org
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AKG promotes skeletal muscle hypertrophy and protein synthesis while it inhibits skeletal muscle protein degradation and muscle atrophy.
“This is consistent with our previous observations that AKG promotes skeletal muscle hypertrophy and protein synthesis (Cai et al, 2016) while it inhibits skeletal muscle protein degradation and muscle atrophy (Cai et al, 2018).”
From Exercise‐induced α‐ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1‐dependent adrenal activation (2020) · cites this paper as Cai et al, 2018
α-Ketoglutarate rescues corticosterone-induced skeletal muscle atrophy in vitro (C2C12 myotubes) and in vivo (C57BL/6J mice) through inhibiting the expression of MuRF1 and MAFbx.
“α-Ketoglutarate rescues corticosterone-induced skeletal muscle atrophy in vitro (C2C12 myotubes) and in vivo (C57BL/6J mice) through inhibiting the expression of MuRF1 and MAFbx [154] (Table 10).”
From Nutraceuticals in the Prevention and Treatment of the Muscle Atrophy (2021) · cites this paper as [154]
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МЕТАБОЛИТЫ ОБМЕНА АМИНОКИСЛОТ И ГОРМОНОВ КАК МАРКЕРЫ ЭФФЕКТИВНОСТИ ТРЕНИРОВОК У ДЕТЕЙ-СПОРТСМЕНОВ
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- Authors
- Cai, X., Yuan, Y., Liao, Z., Xing, K., Zhu, C., Xu, Y., Yu, L., Wang, L., Wang, S., Zhu, X., Gao, P., Zhang, Y., Jiang, Q., Xu, P., & Shu, G.
- Affiliations
- South China Agricultural University (CN)
- Guangdong Provincial Key Laboratory of Animal Nutritional Control College of Animal Science, South China Agricultural University Guangzhou China
- Baylor College of Medicine (US)
- Corresponding author
- Shu, Gang
- ORCID
- Venue
- The FASEB Journal
- Publisher
- Wiley
- Published
- 2017-09-22
- Volume
- 32
- Issue
- 1
- Pages
- 488-499
- ISSN
- 0892-6638 (ISSN-L)
- 1530-6860
- PMC
- PMC6266637
- OpenAlex
- W2758622699
- Cited by
- 65
- References
- 70
- Citations by year
- 2026: 5 · 2025: 10 · 2024: 9 · 2023: 8 · 2022: 9 · 2021: 7 · 2020: 8 · 2019: 7 · 2016: 2
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Update notices
- Open access
- green
- europepmc.org
- Locations
- The FASEB Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Basic Research Program of China (2013CB127306)
- National Natural Science Foundation of China (31572480, 31472105)
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (K99DK107008)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
- Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
- Keywords
- alpha-ketoglutarate, skeletal muscle atrophy, muscle protein degradation, beta2-adrenergic receptor, corticosterone, Duchenne muscular dystrophy, protein stability, muscle atrophy
- MeSH terms
- Animals, Corticosterone, Disease Models, Animal, Ketoglutaric Acids, Male, Mice, Inbred C57BL, Muscle Proteins, Muscular Atrophy, Procollagen-Proline Dioxygenase, Mice, Inbred mdx, Receptors, Adrenergic, beta-2, Muscle, Skeletal, Muscle Fibers, Skeletal, Muscular Dystrophy, Duchenne, Mice, Metabolic Networks and Pathways, Protein Stability, Proteolysis
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