Review synthesizes myokine roles in metabolic regulation, identifying therapeutic potential and mechanistic gaps
Background
Skeletal muscle is now recognized as a dynamic endocrine organ, secreting exercise-induced myokines that coordinate systemic energy homeostasis. These bioactive peptides regulate glucose and lipid metabolism, mitochondrial function, and inflammation, facilitating crucial interorgan communication. Despite their recognized importance, the precise mechanisms and translational readiness of many myokines remain underexplored, presenting a significant gap in developing targeted therapies for metabolic diseases.
Study Design
This comprehensive review synthesizes major advances in exercise-induced myokines since 2018, employing an evidence-based framework to assess mechanistic support and translational relevance. The authors highlight both well-established and emerging myokines, including interleukin-6 (IL-6), irisin, myostatin, and fibroblast growth factor 21 (FGF21), discussing their diverse roles across key target tissues like skeletal muscle, liver, adipose tissue, and bone. They also summarize natural and synthetic compounds reported to modulate myokine expression, secretion, or activity, providing a framework for future therapeutic development.
Results
The review confirms that myokines are critical mediators of muscle-organ crosstalk, regulating glucose and lipid metabolism, mitochondrial function, and inflammation. Key myokines like IL-6, irisin, myostatin, GDF11, IL-15, BDNF, METRNL, SPARC, FGF21, BAIBA, LIF, apelin, and musclin exert diverse effects across skeletal muscle, liver, adipose tissue, and bone. While several myokine axes show therapeutic promise for metabolic disease, the literature reveals substantial heterogeneity. > The current literature indicates substantial heterogeneity in causal evidence, receptor or target certainty, and translational readiness across different myokine pathways. This highlights the need for a more selective view of myokines as biologically heterogeneous mediators. The review also identifies natural and synthetic compounds capable of modulating myokine activity, suggesting avenues for pharmacological intervention.
Key Findings
- Skeletal muscle functions as a dynamic endocrine organ, secreting exercise-induced myokines that regulate systemic energy homeostasis.
- Well-established myokines like IL-6, irisin, myostatin, and FGF21 coordinate glucose/lipid metabolism, mitochondrial function, and inflammation.
- Emerging myokines (e.g., GDF11, BDNF, METRNL, SPARC) also play roles in interorgan communication across muscle, liver, adipose tissue, and bone.
- Natural and synthetic compounds can modulate myokine expression/activity, offering potential for therapeutic development.
- Significant heterogeneity exists in the causal evidence, receptor certainty, and translational readiness of various myokine pathways.
Why It Matters
This review provides a critical update for understanding how exercise benefits metabolic health and offers a roadmap for developing novel therapeutics. Targeting specific myokine pathways could offer new strategies for metabolic disease management, moving beyond general exercise recommendations to precision interventions. While the translational outlook is promising, the identified heterogeneity means that not all myokines are equally ready for clinical application. Future research needs to clarify receptor certainty and causal evidence for individual myokines to develop effective 'exercise mimetics' or myokine-modulating compounds, potentially affecting how we combine or time interventions for optimal metabolic outcomes.
myokines
metabolic regulation
exercise
interleukin-6
irisin
myostatin