Background and aims: Dexamethasone is a common glucocorticoid medication with adverse effects that can cause muscle atrophy, but no drug intervention has been approved or recommended for this condition. KF-8 is a rice bran-derived anti-oxidant peptide that extends the life span of Caenorhabditis elegans. Methods: We established a C. elegans model of dexamethasone-induced myopathy to evaluate the potential therapeutic effects of KF-8 in this model. C. elegans muscle function was assessed in terms of locomotory behaviors including crawling, swimming, burrowing, pharyngeal pumping, and head swing. Muscle actin filament integrity was evaluated using fluorescence imaging. The molecular mechanisms of KF-8 were investigated using transcriptome sequencing, qRT-PCR, RNA interference, and western blot analysis. Results: Dexamethasone disrupted actin filaments in the striated muscles of the body wall and inhibited C. elegans crawling, swimming, burrowing, pharyngeal pumping, and head swing. KF-8 reversed the actin filament disruption and locomotor dysfunction induced by dexamethasone. Transcriptome sequencing, pathway enrichment, and qRT-PCR analyses revealed that KF-8 regulated the locomotion-related genes W04G5.10, vha-12, and ddr-1, as well as age-1 (the catalytic subunit ortholog of PI3K), and akt1. RNA interference, conducted using a genetically engineered E. coli HT115 strain as a food source, confirmed age-1 as a key regulator of locomotor function of C. elegans. Further mechanistic studies with C2C12 myotubes showed that KF-8 regulated the IRS-PI3K-Akt pathway, the master regulator of protein synthesis and degradation. Conclusion: Together, these findings suggest that KF-8 protects against dexamethasone-induced myopathy in C. elegans by regulating locomotion-related genes and the IRS-PI3K-Akt pathway.

In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS) summary statistics of 1325 brain imaging-derived phenotypes (BIDPs) of brain structure from the UK Biobank and GWAS summary datasets of 5 BMD locations, including the total body, femoral neck, lumbar spine, forearm, and heel from the GEFOS Consortium, linkage disequilibrium score regression (LDSC) was conducted to determine the genetic correlations, and Mendelian randomization (MR) was then performed to explore the causal relationship between the BIDPs and BMD. Several sensitivity analyses were performed to verify the strength and stability of the present MR outcomes. To increase confidence in our findings, we also performed confirmatory MR between BIDPs and osteoporosis. LDSC revealed that 1.93% of BIDPs, with a false discovery rate (FDR) < 0.01, were genetically correlated with BMD. Additionally, we observed that 1.31% of BIDPs exhibited a significant causal relationship with BMD (FDR < 0.01) through MR. Both the LDSC and MR results demonstrated that the BIDPs “Volume of normalized brain,” “Volume of gray matter in Left Inferior Frontal Gyrus, pars opercularis,” “Volume of Estimated Total Intra Cranial” and “Volume-ratio of brain segmentation/estimated total intracranial” had strong associations with BMD. Interestingly, our results showed that more left BIDPs were causally associated with BMD, especially within and around the left frontal region. In conclusion, a part of the brain structure causally influences BMD, which may provide important perspectives for the prevention of osteoporosis and offer valuable insights for further research on the brain-bone axis.