Quinine Inhibits Myogenic Differentiation by Disrupting AKT Signaling Pathway

Overview

Journal Toxicol Res

Date 2025 Jan 13

PMID 39802114

Authors

Mi Ran Byun

Sou Hyun Kim

RanJu Woo

Seung Jun Noh

Sang Hoon Joo

Young-Suk Jung

Joon-Seok Choi

Affiliations

Soon will be listed here.

Abstract

Sarcopenia is a disease characterized by decreased muscle fibers and mass. Although it mainly affects the older adults, it can also occur in various age groups as a secondary effect of medications used for treating certain diseases, such as cancer and diabetes. With population aging, sarcopenia has drawn significant attention owing to its increasing prevalence. However, its pathogenesis remains unclear, and no specific treatment is available. Natural products containing bioactive compounds have long been used as therapeutic agents and are crucial sources for drug development. However, the use of drugs derived from natural extracts is limited because of their ambiguous mechanisms of action and potential side effects. Therefore, a systematic analysis of the potential effects of using natural products is required. In this study, we investigated the effects of the antimalarial drug quinine on myogenic differentiation. Our findings revealed that quinine significantly inhibited the expression of marker genes and proteins associated with myogenic differentiation and markedly impaired muscle regeneration following injury. Furthermore, this reduction occurred when quinine selectively decreased the AKT signaling activity. Quinine reduced muscle protein and gene expression by modulating AKT signaling and inhibiting myogenic differentiation and muscle regeneration. Therefore, quinine may cause sarcopenia, and this risk should be considered when using quinine for treatment.

References

Rotwein P, Wilson E . Distinct actions of Akt1 and Akt2 in skeletal muscle differentiation. J Cell Physiol. 2009; 219(2):503-11. PMC: 2750805. DOI: 10.1002/jcp.21692. View

Colley J, Edwards J, Heywood R, Purser D . Toxicity studies with quinine hydrochloride. Toxicology. 1989; 54(2):219-26. DOI: 10.1016/0300-483x(89)90047-4. View

Hollingshead P, Warburton C, Dowd M, Dalton D, Gillett N, Stewart T . IGF-I is required for normal embryonic growth in mice. Genes Dev. 1993; 7(12B):2609-17. DOI: 10.1101/gad.7.12b.2609. View

Santilli V, Bernetti A, Mangone M, Paoloni M . Clinical definition of sarcopenia. Clin Cases Miner Bone Metab. 2015; 11(3):177-80. PMC: 4269139. View

Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M . Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001; 27(2):195-200. DOI: 10.1038/84839. View

Dias D, Urban S, Roessner U . A historical overview of natural products in drug discovery. Metabolites. 2014; 2(2):303-36. PMC: 3901206. DOI: 10.3390/metabo2020303. View

Hawke T, Garry D . Myogenic satellite cells: physiology to molecular biology. J Appl Physiol (1985). 2001; 91(2):534-51. DOI: 10.1152/jappl.2001.91.2.534. View

Mele A, Calzolaro S, Cannone G, Cetrone M, Conte D, Tricarico D . Database search of spontaneous reports and pharmacological investigations on the sulfonylureas and glinides-induced atrophy in skeletal muscle. Pharmacol Res Perspect. 2014; 2(1):e00028. PMC: 4186404. DOI: 10.1002/prp2.28. View

Verdijk L, Snijders T, Drost M, Delhaas T, Kadi F, van Loon L . Satellite cells in human skeletal muscle; from birth to old age. Age (Dordr). 2013; 36(2):545-7. PMC: 4039250. DOI: 10.1007/s11357-013-9583-2. View

10.

Wilson E, Hsieh M, Rotwein P . Autocrine growth factor signaling by insulin-like growth factor-II mediates MyoD-stimulated myocyte maturation. J Biol Chem. 2003; 278(42):41109-13. DOI: 10.1074/jbc.C300299200. View

11.

Rosenberg I . Sarcopenia: origins and clinical relevance. J Nutr. 1997; 127(5 Suppl):990S-991S. DOI: 10.1093/jn/127.5.990S. View

12.

Grounds M, Yablonka-Reuveni Z . Molecular and cell biology of skeletal muscle regeneration. Mol Cell Biol Hum Dis Ser. 1993; 3:210-56. DOI: 10.1007/978-94-011-1528-5_9. View

13.

Druilhe P, Brandicourt O, CHONGSUPHAJAISIDDHI T, Berthe J . Activity of a combination of three cinchona bark alkaloids against Plasmodium falciparum in vitro. Antimicrob Agents Chemother. 1988; 32(2):250-4. PMC: 172144. DOI: 10.1128/AAC.32.2.250. View

14.

Achan J, Talisuna A, Erhart A, Yeka A, Tibenderana J, Baliraine F . Quinine, an old anti-malarial drug in a modern world: role in the treatment of malaria. Malar J. 2011; 10:144. PMC: 3121651. DOI: 10.1186/1475-2875-10-144. View

15.

Hastings R, Massopust R, Haddix S, Lee Y, Thompson W . Exclusive vital labeling of myonuclei for studying myonuclear arrangement in mouse skeletal muscle tissue. Skelet Muscle. 2020; 10(1):15. PMC: 7204059. DOI: 10.1186/s13395-020-00233-6. View

16.

Schiaffino S, Dyar K, Ciciliot S, Blaauw B, Sandri M . Mechanisms regulating skeletal muscle growth and atrophy. FEBS J. 2013; 280(17):4294-314. DOI: 10.1111/febs.12253. View

17.

Zammit P . Function of the myogenic regulatory factors Myf5, MyoD, Myogenin and MRF4 in skeletal muscle, satellite cells and regenerative myogenesis. Semin Cell Dev Biol. 2017; 72:19-32. DOI: 10.1016/j.semcdb.2017.11.011. View

18.

Tureckova J, Wilson E, Cappalonga J, Rotwein P . Insulin-like growth factor-mediated muscle differentiation: collaboration between phosphatidylinositol 3-kinase-Akt-signaling pathways and myogenin. J Biol Chem. 2001; 276(42):39264-70. DOI: 10.1074/jbc.M104991200. View

19.

Schiaffino S, Mammucari C . Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet Muscle. 2011; 1(1):4. PMC: 3143906. DOI: 10.1186/2044-5040-1-4. View

20.

Hernandez-Hernandez J, Garcia-Gonzalez E, Brun C, Rudnicki M . The myogenic regulatory factors, determinants of muscle development, cell identity and regeneration. Semin Cell Dev Biol. 2017; 72:10-18. PMC: 5723221. DOI: 10.1016/j.semcdb.2017.11.010. View