Targeting muscle-bone crosstalk with hormone-like peptides: Systems approach reveals RGHGP-mediated suppression of...

Clinical evidence suggests a strong association between bone and muscle; however, the underlying mechanisms beyond the physiological relationship remain unclear.

To explore the pathological changes between bone and muscle using a bilateral ovariectomy (OVX) model and to evaluate the therapeutic potential of Rengong hugu power (RGHGP) as a peptide-derived intervention in regulating muscle-bone health.

Dual-tissue transcriptomics, network construction, and therapeutic intervention experiments were performed. Tissue-specific ligand-receptor and signaling pathway interaction networks were constructed based on dual-tissue transcriptomics sequencing data. Crucial ligands and receptors were identified to provide a foundation for interorgan communication. RGHGP was administered to regulate muscle-bone health, and its role as a ligand-like molecule binding to major receptors and pathways was verified. Potential peptides coordinating muscle-bone health were predicted. Weight, mass, imaging, and histopathological changes were assessed. TRAP staining, protein-peptide docking, and in vitro assays were used to evaluate the role of RGHGP and Laminin subunit beta 1 (LAMB1) on bone metabolism and osteoclastogenesis.

OVX induced osteoporosis and muscle atrophy, whereas RGHGP reversed these pathological changes. Six myokines, represented by LAMB1 and connective tissue growth factor (CTGF), mediated bone metabolism through the mitogen-activated protein kinases(MAPK) pathway. In the OVX model, muscle-secreted LAMB1 and CTGF were upregulated in bone, activating MAPK signaling (phosphorylation of p38 and JNK) and increasing osteoclasts, as detected by TRAP staining. RGHGP treatment repressed LAMB1/CTGF expression, MAPK pathway activation, and osteoclast number. In vitro studies showed that the recombinant protein LAMB1 (rLAMB1) promotes osteoclast formation by activating the MAPK pathway. In contrast, the therapeutic peptide RGHGP effectively blocks this process. This therapeutic effect is structurally supported by protein-peptide docking, which confirmed the ability of RGHGP to bind key receptors in MAPK receptor signaling.

This study establishes a ligand (LAMB1)-receptor-pathway (MAPK) model for muscle-bone crosstalk, highlighting the role of muscle-derived ligands in counteracting muscle atrophy and regulating osteoclasts and osteoporosis. RGHGP-derived peptides act as muscle-mimetic ligands, reconfiguring muscle-bone crosstalk, and modulating skeletal remodeling. Furthermore, this reconfigured crosstalk influences energy metabolism, a process intrinsically linked to bone remodeling and overall musculoskeletal homeostasis. LAMB1 is identified as a pivotal mediator of integrated bone-muscle homeostasis.