Aging is an important risk factor for cardiovascular disease, and ageing-related cardiac dysfunction is a major determinant of morbidity and mortality among the elderly population. Although little is known about all the exact molecular and cellular bases, chronic cardiac inflammation has been linked to the pathogenesis of aging-related cardiac dysfunction in a way that relies on inflammation.
Previous studies by researchers have determined that the fibronectin type III domain contains 5 (FNDC5) and its lysed form iris is a cardiomyotropic protector against doxorubicin-induced cardiomyopathy.
Image source: https://doi.org/10.1111/acel.13556
Recently, researchers from the Department of Cardiology of Wuhan University People's Hospital published an article titled "Fibronectin type III domain- containing 5 improves aging- related cardiac dysfunction in mice" in the journal Agg cell. The study demonstrates that FNDC5 improves aging-related cardiac dysfunction by activating AMPKα, and it could be a promising therapeutic target to support cardiovascular health in older populations.
In this study, researchers overexpressed FNDC5 to senescent or paired young mice through adeno-associated virus serotype 9 (AAV9) vectors, or injected subcutaneously with iris to reveal the role of FNDC5 in aging-related cardiac dysfunction.
To verify the participation of nucleotide-bound oligomeric domain-like receptors (NLRP3) containing pyrrole domain 3 (NLRP3) and adenylate-activated protein kinase α (AMPKα), the researchers used NLRP3 or AMPKα2 global gene knockout mice. In addition, infant mice inject AAV9-FNDC5 for 12 months to determine the prophylactic effect of FNDC5. In addition, the researchers stimulated newborn rat cardiomyocytes with tumor necrosis factor-α (TNF-α) to observe the role of FNDC5 in vitro.
The researchers found that FNDC5 was downregulated in aging hearts. Cardiac-specific overexpression of FNDC5 or perfusion of iris significantly inhibits NLRP3 inflammation of small bodies and heart inflammation, thereby reducing cardiac remodeling and dysfunction associated with aging. In addition, iris therapy can also inhibit the cellular senescence of TNF-α stimulated cardiomyocytes in vitro. In terms of mechanism, FNDC5 activates AMPKα by blocking lysozyme degradation of glucagon-like peptide-1 receptors. What's more, transferring the FNDC5 gene early in life can delay the occurrence of cardiac insufficiency during aging.
FNDC5 blocks heart remodeling associated with aging in mice
Taken together, this study demonstrates that FNDC5 improves aging-related myocardial dysfunction by activating AMPKα, and it could be a promising therapeutic target to support cardiovascular health in older populations.
bibliography:
Can Hu et al. Fibronectin type III domain- containing 5 improves aging- related cardiac dysfunction in mice. Aging Cell. 2022 Feb 15;e13556. doi: 10.1111/acel.13556.