How does muscle aging affect metabolic function? The latest publication by Josef M. Penninger, an academician of the Austrian Academy of Sciences

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As the years go by, our muscles gradually lose the vitality of our youth, a phenomenon known as muscle aging. It not only affects our athletic ability, but is also closely related to a variety of chronic diseases (such as type 2 diabetes). Muscles play a central role in regulating whole-body metabolism, especially in glucose metabolism.

Although scientists are still actively exploring the complex issue of how muscle aging affects metabolic function , the latest research results have begun to reveal a key molecule in the process - glycerylphosphocholine diesterase 1 (Gpcpd1) . This enzyme, which is highly expressed in muscle tissue, is responsible for breaking down glycerylphosphocholine (GPC) and plays a vital role in maintaining glucose metabolism balance.

Recently, Nature Aging published an in-depth study on muscle aging and its impact on glucose tolerance. The Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism, providing a new perspective for us to understand the biological mechanisms behind muscle aging.

Related research review

Muscle aging is closely associated with a variety of molecular and metabolic disorders that may affect muscle function and systemic metabolism. For example, Demontis et al. (2013) have shown that with aging, the muscle's ability to utilize glucose decreases significantly, which may lead to disorders in systemic glucose metabolism (Demontis, F., et al., 2013). In addition, Chia et al. (2018) found that this decline in metabolic capacity is associated with aging, further emphasizing the impact of muscle aging on glucose metabolism (Chia, CW, et al., 2018).

At the molecular level, the study by Houtkooper et al. (2011) showed that GPC, as a substrate of the Gpcpd1 enzyme, was significantly increased in the muscles of aged mice, which may be related to metabolic changes during muscle aging (Houtkooper, RH, et al., 2011). In addition, the study by Pilling et al. (2016) revealed the association between single nucleotide polymorphisms (SNPs) near the human GPCPD1 gene and longevity, which provided new clues for understanding the role of Gpcpd1 in human health and lifespan (Pilling, LC, et al., 2016). These research results provide a solid theoretical basis for this article, prompting researchers to further explore the role of Gpcpd1 in muscle aging, especially its impact on the regulation of glucose metabolism.

Changes in the Gpcpd1 enzyme during aging

The research team first observed the changes in Gpcpd1 mRNA expression and GPC metabolite levels with age in a mouse model. They found that Gpcpd1 mRNA levels in skeletal muscle of old mice (24 months old) decreased significantly compared with young mice (6 months old), leading to GPC accumulation in the muscle. This suggests that it plays a key role in muscle aging and decreased metabolic function.

Gpcpd1 mRNA levels decreased and GPC accumulation was significant in skeletal muscle of aged mice To investigate the physiological effects behind Gpcpd1 deficiency, the researchers created several tissue-specific Gpcpd1-deficient mouse models, including muscle, liver, or adipose tissue. The effects of Gpcpd1 deficiency on mouse metabolism were further evaluated by glucose tolerance tests, insulin signaling analysis, transcriptome analysis, and lipidomics analysis.

The study found that in muscle-specific Gpcpd1 knockout mice (i.e. mice lacking Gpcpd1), glucose tolerance was further deteriorated when they were fed a high-sugar or high-fat diet, suggesting that Gpcpd1 plays an important role in maintaining normal glucose metabolism in muscle , and its deficiency exacerbates metabolic problems caused by diet.

The above figures reveal that muscle-specific Gpcpd1-deficient mice have impaired glucose tolerance under high-sugar and high-fat diet conditions. More importantly, two independent studies of adults (aged between 44 and 70 years old) revealed a significant trend: with age, the expression level of Gpcpd1 mRNA in muscle decreased significantly, suggesting a weakening of Gpcpd1 enzyme activity. At the same time, there was a corresponding increase in the levels of GPC and its phosphodiester derivatives in the muscles of sedentary elderly people. In addition, compared with non-diabetic patients, the accumulation of GPC and its phosphodiester derivatives in the skeletal muscle of patients with type 2 diabetes is more significant.

Age-dependent changes in muscle GPCPD1 mRNA levels in two independent adult cohorts

Comparison of muscle GPC and GPC-phosphodiester levels in healthy volunteers and patients with type 2 diabetes GPCpd1 as a potential target for anti-aging

The study suggests that the Gpcpd1-GPC metabolic pathway plays an important role in regulating glucose homeostasis and that the function of this pathway may be impaired during aging, suggesting that Gpcpd1 may be a potential anti-aging therapeutic target.

The corresponding author of the article, Academician Josef M. Penninger, is a member of the Austrian Academy of Sciences, a member of the European Academy of Sciences, and one of the world's leading medical scientists. He has made many groundbreaking research results and developed new drugs that can benefit millions of patients . Academician Josef M. Penninger pointed out: "Our study reveals the key role of the glycerophosphorylcholine (GPC) degradation pathway in muscle tissue in the aging process and highlights the potential impact of health interventions, such as exercise or intermittent fasting, on this pathway. " He further stated: " Our long-term goal is to develop therapeutic strategies targeting these identified pathways to improve glucose metabolism in the elderly and prevent and treat aging-related metabolic diseases such as type 2 diabetes. " This groundbreaking research by Professor Penninger and his team has undoubtedly brought new hope to the field of aging research and provided strong scientific support for future health intervention strategies.

References

[1] Cikes D, Leutner M, Cronin SJF, Novatchkova M, Pfleger L, Klepochová R, Lair B, Lac M, Bergoglio C, Viguerie N, Dürnberger G, Roitinger E, Grivej M, Rullman E, Gustafsson T, Hagelkruys A, Tavernier G, Bourlier V, Knauf C, Krebs M, Kautzky-Willer A, Moro C, Krssak M, Orthofer M, Penninger JM. Gpcpd1-GPC metabolic pathway is dysfunctional in aging and its deficiency severely perturbs glucose metabolism. Nat Aging. 2024 Jan;4(1):80-94. doi: 10.1038/s43587-023-00551-6. Epub 2024 Jan 18. PMID: 38238601.

[2] Demontis F, Piccirillo R, Goldberg AL, Perrimon N. Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models. Dis Model Mech. 2013 May;6(5):1339-52. doi: 10.1242/dmm.010244. Epub 2013 Apr 22. PMID: 23375909.

[3] Chia CW, Egan JM, Ferrucci L. Age-related changes in glucose metabolism, hyperglycemia, and cardiovascular risk. Circ Res. 2018 Aug 3;123(3):886-904. doi: 10.1161/CIRCRESAHA.118.312439. Epub 2018 Jun 21. PMID: 30309759.

[4] Houtkooper RH, et al. The metabolic footprint of aging in mice. Sci Rep. 2011;1:134. doi: 10.1038/srep00134. Epub 2011 Apr 21. PMID: 22190332.

[5] Pilling LC, et al. Human longevity is influenced by many genetic variants: evidence from 75,000 UK Biobank participants. Aging (Albany NY). 2016 Jun;8(6):547-60. doi: 10.18632/aging.100962. Epub 2016 Apr 28. PMID: 27176760.

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