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 lifespan of Caenorhabditis elegans. 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, quantitative real-time PCR (qRT-PCR), RNA interference, and Western blot analysis. 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 phosphatidylinositol 3-kinase (PI3K)), and akt1. RNA interference, conducted using a genetically engineered Escherichia 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. 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.

The NRF2 pathway is a metabolic- and redox-sensitive signaling axis in which the transcription factor controls the expression of a multitude of genes that enable cells to survive environmental stressors, such as oxidative stress, mainly by inducing the expression of cytoprotective genes. Basal NRF2 levels are maintained under normal physiological conditions, but when exposed to oxidative stress, cells activate the NRF2 pathway, which is crucial for supporting cell survival. Recently, the NRF2 pathway has been found to have novel functions in metabolic regulation and interplay with other signaling pathways, offering novel insights into the treatment of various diseases. Numerous studies have shown that targeting its pathway can effectively investigate the development and progression of age-related musculoskeletal diseases, such as sarcopenia, osteoporosis, osteoarthritis, and intervertebral disc degeneration. Appropriate regulation of the NRF2 pathway flux holds promise as a means to improve musculoskeletal function, thereby providing a new avenue for drug treatment of age-related musculoskeletal diseases in clinical settings. The review summarized an overview of the relationship between NRF2 and cellular processes such as oxidative stress, apoptosis, inflammation, mitochondrial dysfunction, ferroptosis, and autophagy, and explores the potential of targeted NRF2 regulation in the treatment of age-related musculoskeletal diseases.

Osteoarthritis (OA) is a common chronic joint disease characterized by articular cartilage degeneration, subchondral sclerosis, synovitis, and osteophyte formation. OA is associated with disability and impaired quality of life, particularly among the elderly. Leptin, a 16-kD non-glycosylated protein encoded by the obese gene, is produced on a systemic and local basis in adipose tissue and the infrapatellar fat pad located in the knee. The metabolic mechanisms employed by leptin in OA development have been widely studied, with attention being paid to aging as a corroborative risk factor for OA. Hence, in this review, we have attempted to establish a potential link between leptin and OA, by focusing on aging-associated mechanisms and proposing leptin as a potential diagnostic and therapeutic target in aging-related mechanisms of OA that may provide fruitful guidance and emphasis for future research.

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.