3.3 The miR-222 Pathway

MicroRNAs (miRNAs) are short, non-coding RNAs which help regulate gene expression by repressing or degrading target messenger RNA (mRNA) and can be used as biomarkers (Riedel et. al). Also, miRNAs are known to assist in the regulation of cardiac hypertrophic process by negatively or positively modulating hypertrophic signaling (Chen et. al). One of the main pathways involved in exercise-induced cardiac growth is through miR-222 as it an important regulator of cardiac growth. miR-222 is a highly conserved miRNA cluster located on the X chromosome which could protect mammals against pathological cardiac remodeling and serve as a biomarker (Schmitz et. al) (Lui et. al).

Studies have shown miR-222 vital for exercise-induced cardiomyocyte growth and proliferation in the adult mammalian heart (Liu et. al) (Vujic et. al). In a study by Liu et. al 2015, they found increased expression of miR-222 caused an increase in cardiomyocytes, the markers of cardiomyocyte proliferation and in cell numbers. It helped protect against pathogenic ventricular remodeling and cardiac dysfunction suffered after an ischemic injury. The inhibition of miR-222 in vivo reduced cardiomyocyte size, proliferation in addition to blocking cardiac and cardiomyocyte growth in response to exercise in mice. In a study conducted by Vujic et al. 2018, they found induced miR-222 expression levels in exercised adult mouse hearts and it regulated cardiomyogenesis. They identified the direct downstream targets of miR-222 modulating cardiomyocyte phenotypes such as HIPK1 which is a protein kinase involved in the regeneration of cardiomyocytes. When miR-222 was inhibited, HIPK1 expression was significantly elevated. This study supported the idea in which exercise can stimulate endogenous regenerative abilities in the adult mammalian heart (Vujic et. al).