From Skeletal Muscle to Myocardium: Molecular Mechanisms of Exercise-Induced Irisin Regulation of Cardiac Fibrosis

Figures

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  Figure 1. Mechanisms and Current Treatments of Cardiac Fibrosis. This figure outlines the mechanisms, detection methods, and treatment strategies for cardiac fibrosis. miR-21 promotes fibrosis progression by regulating the transforming growth factor-beta (TGF-β) signaling pathway, while miR-29 regulates the metabolic balance of the extracellular matrix (ECM). Oxidative stress and inflammatory factors further exacerbate pathological changes. Magnetic Resonance Imaging (MRI) and serum biomarkers can be used to assess fibrosis. Biomarkers include procollagen type I N-terminal propeptide (PINP), procollagen type II N-terminal propeptide (PIINP), and matrix metalloproteinases (MMPs). Drugs such as Losartan, N-acetylcysteine (NAC), and regenerative medicine techniques provide potential therapeutic options. This figure was created in BioRender. Wang, Z. (2025). https://BioRender.com/n80e582, accessed on 7 April 2025.

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  Figure 2. Mechanisms Underlying Irisin-Mediated Cardioprotection. This figure outlines how Irisin exerts cardioprotective effects by inhibiting inflammation, alleviating oxidative stress, maintaining mitochondrial dynamics, suppressing apoptosis, and mitigating microvascular damage. Moreover, Irisin protects cardiac function by reducing fibrosis through the inhibition of the TGF-β signaling pathway. This figure was created in BioRender. Wang, Z. (2025) https://BioRender.com/x59p404, accessed on 7 April 2025.

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  Figure 3. Comprehensive mechanism by which Irisin influences fibrosis Via Sirtuin 1 (Sirt1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)/nuclear respiratory factor 1 (NRF-1), and related pathways. This figure summarizes how Irisin significantly reduces the expression of fibrosis-related genes by directly inhibiting TGF-β activation and blocking Smad signaling through receptor binding. Additionally, Irisin activates Sirt1, which mediates the deacetylation of Smad3, further suppressing Smad complex formation. By regulating the PGC-1α/NRF-1 pathway, Irisin helps maintain mitochondrial homeostasis, while enhancing mitophagy through the PTEN-induced kinase 1 (PINK1)/Parkin pathway to clear damaged mitochondria and improve intracellular equilibrium. Collectively, these actions inhibit fibrotic progression, mitigate tissue damage, and offer new insights for the treatment of cardiac fibrosis. This figure was created in BioRender. Wang, Z. (2025) https://BioRender.com/s24j371, accessed on 7 April 2025.

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  Figure 4. Exercise-Induced Irisin Release and Its Role in Cardiac Fibrosis. Exercise (high-intensity, resistance, and long-term training) activates Irisin secretion from skeletal muscle. Irisin enters the bloodstream and exerts systemic effects. In the heart, it binds to integrin receptors, modulating the TGF-β/Smad signaling pathway to inhibit fibrosis. Additionally, Irisin functions through autocrine and paracrine mechanisms. It also influences thermogenesis in adipose tissue and bone remodeling, highlighting its multifunctional role. This figure was created in BioRender. Wang, Z. (2025) https://BioRender.com/o81x119, accessed on 7 April 2025.