Black ginger-derived compound promotes muscle growth via GPR97 receptor

Professor Ryoichi Yamaji, Graduate Student Shuhei Fujita, Associate Professor Naoki Harada, and Assistant Professor Tomoya Kitakaze of the Graduate School of Agriculture, Osaka Metropolitan University, have elucidated the molecular mechanism by which the natural black ginger-derived compound HMF (5-hydroxy-7-methoxyflavone) induces hypertrophy of skeletal muscle cells through analyses using mouse-derived myotube cells. As a result of their analyses, they discovered that the receptor protein GPR97, located on the cell membrane, promotes myotube hypertrophy. Furthermore, they identified the "GPR97-Gα12-mTORC1 pathway" as a novel signaling pathway involved in muscle hypertrophy mediated by this receptor and revealed that HMF activates this pathway, thereby promoting protein synthesis and inducing muscle hypertrophy. The findings were published online in Archives of Biochemistry and Biophysics.

Skeletal muscle is the largest tissue in the human body, accounting for approximately 40% of body weight, and plays important roles not only in movement but also in sugar and lipid metabolism. On the other hand, decreases in skeletal muscle mass caused by aging, lack of exercise, prolonged bed rest, and other factors lead to declines in both physical and metabolic function. Therefore, elucidation of the molecular mechanisms that maintain and increase skeletal muscle mass is needed.

The research group has previously reported that HMF, a natural compound derived from black ginger, induces hypertrophy of skeletal muscle cells and suppresses muscle atrophy in accelerated-aging model mice. However, the molecular target through which HMF induces muscle hypertrophy had remained unclear.

This time, the researchers analyzed the mechanism by which HMF induces muscle hypertrophy using mouse-derived myotube cells. As a result, they discovered that the receptor protein GPR97, located on the cell membrane, promotes myotube hypertrophy. Furthermore, suppressing GPR97 expression caused myotube atrophy and abolished the muscle-hypertrophic effect of HMF.

Conversely, increasing GPR97 expression promoted muscle hypertrophy, and HMF was found to further enhance this effect. Further analysis revealed that HMF activates the G protein Gα12 via GPR97 and induces muscle hypertrophy by transmitting signals to mTORC1, which regulates protein synthesis. In addition, administration of HMF to mouse skeletal muscle activated mTORC1 signaling.

This result indicates that the effect occurs not only in cultured cells but also in living tissue.

Next, the researchers investigated how Gα12 induces muscle hypertrophy. Until now, Gα12 was thought to exert its effects mainly through the RhoA-SRF pathway. However, although the present study confirmed that HMF activates the RhoA-SRF pathway, inhibition of this pathway did not suppress muscle hypertrophy. In contrast, inhibition of either Gα12 or mTORC1, a signaling pathway that regulates protein synthesis, abolished HMF-induced muscle hypertrophy.

These results indicate that HMF promotes protein synthesis and induces muscle hypertrophy not through the conventionally recognized Gα12-RhoA-SRF pathway, but through the newly identified GPR97-Gα12-mTORC1 pathway.

This study has revealed a novel molecular pathway that promotes skeletal muscle hypertrophy. The findings are expected to contribute to advances in research aimed at preventing and improving age-related sarcopenia and muscle atrophy caused by prolonged bed rest. In addition, the newly identified GPR97-Gα12-mTORC1 pathway could serve as a new target for maintaining and increasing skeletal muscle mass. Future studies will need to investigate in detail how HMF activates Gα12 via GPR97.

The findings are also expected to support the research and development of functional foods and dietary supplements that help maintain muscle mass.

Journal Information
Publication: Archives of Biochemistry and Biophysics
Title: GPR97-Gα12-mTORC1 signaling drives myotube hypertrophy: identification of 5-hydroxy-7-methoxyflavone as a pathway activator
DOI: 10.1016/j.abb.2026.110964