Potential Molecular Mechanism of FNDC4 Protection Against Aging in the Heart

Corresponding Author

Aging is an independent risk factor for the development of cardiovascular disease (CVD), including heart failure.¹ Cardiac aging is associated with a cell autonomous decline in energy metabolism and mitochondrial function. Aging also increases senescence of cardiomyocytes, characterized by the presence of DNA damage and the senescence associated secretory phenotype, which promotes inflammation and fibrosis through paracrine mechanisms.² Eventually, both cell autonomous and noncell autonomous mechanisms acting in concert induce cardiac remodeling and promote heart failure.¹ Upstream mechanisms that initially trigger the decline in energy metabolism and tissue remodeling during cardiac aging remain poorly understood. Previous studies have shown the presence of circulating rejuvenating factors, such as GDF11, that are down-regulated during aging, which in turn plays an important role in regulating aging in multiple organs, including the heart.³ Such mechanisms are attractive candidates for clinical interventions because their levels in the plasma can be modified relatively easily.

Fibronectin type III domain containing 4 (FNDC4) is a type I transmembrane glycoprotein mainly expressed in the liver and brain, but also in the heart, skeletal muscle, and adipose tissue.⁴ FNDC4 can be released into the bloodstream as a soluble factor, thereby acting as an autocrine, paracrine, or endocrine factor through its binding to GPR116, a putative transmembrane G-protein coupled receptor. FNDC4 has multiple biological functions, including regulation of inflammation, lipid glucose metabolism, tumorigenesis, skeletal muscle differentiation, and browning of adipocytes.^5,6 Importantly, previously reported functions of FNDC4 are generally salutary in many organs and, thus, it may act as a protective mechanism in the heart as well. FNDC5, another member of the FNDC family and the precursor of irisin, possesses a high homology with FNDC4 and also inhibits inflammation and oxidative damage.

In the study by Zhang et al⁷ in this issue of JACC: Basic to Translational Science, the authors discovered that FNDC4 levels in both cardiomyocytes and the plasma decrease with age, which correlated with poor cardiac function. Restoring FNDC4 in cardiomyocytes alleviated aging-related cardiac remodeling and dysfunction, improved mitochondrial function, and reduced lipid accumulation. On the other hand, knock-down of FNDC4 in cardiomyocytes exacerbated cardiac and mitochondrial dysfunction in aging hearts. FNDC4 activated the AMPKα/PPARα signaling pathway, thereby enhancing mitochondrial function and lipid metabolism. Activation of PPARα led to a decrease in lipid accumulation and reduced inflammation, suggesting that FNDC4 prevents inflammaging. Administration of recombinant FNDC4 protein significantly reduced senescence and fibrosis in the heart; improved cardiac function in aging mice without adverse effects, including hepatic or muscular injuries; and even protected renal function during aging. These results are consistent with the notion that FNDC4 acts as an autocrine/paracrine factor controlling cardiac aging (Figure 1).

Figure 1.

The Function of FNDC4 During Aging

Fibronectin type III domain containing 4 (FNDC4) may act as an autocrine/paracrine or endocrine factor to affect various cellular responses, through binding to GPR116, a putative receptor, and activation of the AMPK-Sirt1 or other signaling mechanisms, in various organs. FNDC4 generally plays a salutary role through regulation of energy metabolism, mitochondrial biogenesis, and inflammation. Although ischemia/reperfusion up-regulates FNDC4, aging and obesity down-regulate FNDC4. AMPK = AMP-activated protein kinase; ER = endoplasmic reticulum; FOXO3 = forkhead box O3; GPR116 = G protein-coupled receptor 116; HIF1α = hypoxia-inducible factor 1α; I/R = ischemia/reperfusion; NFκB = nuclear factor kappa B; PPARα = peroxisome proliferator-activated receptors α; Sirt1 = sirtuin 1.

The authors’ findings are significant because the study clearly demonstrated that FNDC4 is an important endogenous mechanism preventing aging. It warrants further study to investigate the mechanism regulating the cardiac levels of FNDC4 during aging and the molecular signaling mechanism mediating its protective effect.

The study also raises interesting questions for future investigation. First, FNDC4 has a signal peptide and can act as a secreted protein. The authors found that the plasma level of FNDC4 declines during aging in humans. This raises a question as to whether FNDC4 acts as a major anti-aging endocrine factor, like GDF11, preventing aging in other organs as well. Since FNDC4 inhibits inflammation and insulin resistance, reduces lipogenesis, and induces fat browning in other tissues,⁵ FNDC4 may act as a cardiokine. In this study, the authors only tested the effect of cardiomyocyte-specific rescue of FNDC4 and demonstrated the autocrine/paracrine effect of FNDC4. Thus, it would be important to examine the effects of systemic application of recombinant FNDC4 during aging in both the heart and other organs, besides kidney protection, and its role as an endocrine factor. The authors show that cardiomyocytes are the major cell type producing FNDC4 in the heart. However, FNDC4 also exists in other organs.⁵ Thus, it would be of great interest to test the major sources of FNDC4 in the plasma.

Second, the decline in mitochondrial function and energy metabolism is a major mechanism of aging in the heart. Although the authors propose that lipotoxicity and consequent inflammation and senescence are the major mechanisms mediating the effect of aging, other mechanisms, including energy maintenance through ATP and/or increased energy consumption through uncoupling mechanisms, need to be clarified.^5,8 In adipocytes, FNDC4 acts as a paracrine factor to promote energy consumption and fat browning.⁵ Whether the FNDC4-PPARα pathway includes a direct transcriptional mechanism regulating mitochondrial biogenesis needs to be determined, because mitochondria are secondarily affected by many mechanisms. Interestingly, a previous study suggested that pharmacological interventions to stimulate PPARα and RXRs promote transcription of adipokines, including FNDC4 and GDF11, thereby stimulating energy-wasting enzyme cycles to promote energy expenditure and oxygen consumption in adipocytes.⁹ It would be interesting to test whether FNDC4 also acts a cardiokine to promote energetic remodeling in cardiomyocytes. In addition, testing whether stimulation of PPARα/RXRs with synthetic agonists can up-regulate FNDC4 in cardiomyocytes⁹ would be of great interest.

Finally, FNDC4 and FNDC5/irisin are also affected in other cardiac conditions, including obesity (down-regulation) and ischemia/reperfusion (up-regulation).¹⁰ The authors propose that AMPK and Sirt1 act as upstream regulators of PPARα. Because AMPK and Sirt1 have a wide variety of functions relevant in aging, including autophagy and epigenetics, further investigation is needed to clarify the function of FNDC4 in cardiomyocytes.

In summary, the study by Zhang et al⁷ suggests that FNDC4 is an important regulator of cardiac aging. In particular, they showed interesting effects of FNDC4 upon metabolism and inflammaging, major regulators of aging. Further investigations are needed to clarify both the upstream and downstream mechanisms through which FNDC4 affects energy metabolism. In addition, clarifying whether FNDC4 acts as endocrine factor, like GDF11, regulating aging in various organs, and whether the plasma level of FNDC can be used as a biomarker of aging would be of great interest.

Funding Support and Author Disclosures

This work was supported in part by U.S. Public Health Service Grants HL91469, HL112330, HL138720, HL144626, and HL150881 (to Dr Sadoshima); American Heart Association Postdoctoral Fellowship 25POST1369529 (to Dr Matsushita); and Merit Award 20 MERIT35120374 (to Dr Sadoshima).