Muscle-Bone Interactions and Crosstalk Mechanisms

Muscle and bone constitute a multifunctional unit whose integrity is maintained through both mechanical forces and biochemical signalling. Mechanical loading generated by muscle contraction imposes strains on bone that are sensed by mechanosensitive cells, leading to adaptive remodelling and maintenance of skeletal strength. Conversely, bone-derived factors influence muscle metabolism and function, establishing a reciprocal relationship. Beyond physical interaction, both tissues act as endocrine organs, secreting myokines and osteokines that traverse the circulation or travel in extracellular vesicles to modulate cell differentiation, growth and repair in the partner tissue. Key pathways involved include the Wnt/β-catenin axis, transforming growth factor-β family members and inflammatory cytokines. Dysregulation of this intertissue communication contributes to age-related musculoskeletal decline, metabolic bone diseases and muscle wasting. Understanding the integrated network of mechanotransduction, paracrine and endocrine signals is critical for developing interventions that preserve mobility and skeletal integrity throughout life.

Research from Nature Portfolio

Advanced metabolomic profiling has revealed that specific aminobutyric acid isomers in serum correlate with bone mineral density, fracture risk and physical activity. γ-Aminobutyric acid (GABA) and D-beta-aminoisobutyric acid (D-BAIBA) show positive associations with skeletal health and exercise status, suggesting their utility as minimally invasive biomarkers for bone quality. Genetic variants in enzymes regulating these metabolites further link muscle activity to bone turnover, opening avenues for diagnostic and therapeutic strategies.

Investigations into myostatin (GDF8), a potent myokine inhibitor of muscle growth, have demonstrated its dual role in bone regeneration, particularly under diabetic conditions. Local administration of the myostatin antagonist follistatin in a murine tibial defect model restored defective osteogenic differentiation and mineralisation, achieving marked improvements in bone repair. These findings underscore myostatin’s significance in muscle-bone crosstalk and validate its inhibition as a promising approach to enhance skeletal regeneration in metabolic disease.

Muscle-Bone Interactions and Crosstalk Mechanisms publication trend

The graph below shows the total number of articles in muscle-bone interactions and crosstalk mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Myokine: A bioactive protein secreted by muscle cells that influences distant tissues, including bone.

Osteokine: A signalling molecule produced by bone cells that modulates muscle function and systemic metabolism.

Exosome: A small extracellular vesicle carrying proteins, lipids and nucleic acids for intercellular communication.

Mechanotransduction: The process by which cells convert mechanical stimuli into biochemical signals to regulate tissue adaptation.

Osteosarcopenia: The concomitant occurrence of bone loss (osteoporosis) and muscle wasting (sarcopenia) in ageing or disease.

Myostatin (GDF8): A transforming growth factor-β family member that inhibits muscle growth and affects bone regeneration.

Aminobutyric acids: Metabolites such as GABA and BAIBA that serve as potential biomarkers linking muscle activity to bone health.

References

1. Interactions between Muscle and Bone—Where Physics Meets Biology. Biomolecules (2020).
2. Crosstalk Between MLO Y4 Osteocytes and C2C12 Muscle Cells Is Mediated by the Wnt/β Catenin Pathway. JBMR Plus (2017).
3. Muscle–Bone Crosstalk: Emerging Opportunities for Novel Therapeutic Approaches to Treat Musculoskeletal Pathologies. Biomedicines (2017).
4. Bone and Muscle Crosstalk in Aging. Frontiers in Cell and Developmental Biology (2020).
5. Quantification of aminobutyric acids and their clinical applications as biomarkers for osteoporosis. Communications Biology (2020).
6. Muscle-Bone Crosstalk in the Masticatory System: From Biomechanical to Molecular Interactions. Frontiers in Endocrinology (2021).
7. Role of Physical Activity in Bone–Muscle Crosstalk: Biological Aspects and Clinical Implications. Journal of Functional Morphology and Kinesiology (2021).
8. Inhibition of GDF8 (Myostatin) accelerates bone regeneration in diabetes mellitus type 2. Scientific Reports (2017).