Identification of the Mtus1 Splice Variant as a Novel Inhibitory Factor Against Cardiac Hypertrophy

Abstract

BackgroundIn cardiac hypertrophy and failure, there is a widespread alteration in mRNA splicing, but the role of splice variants in cardiac hypertrophy has not yet been fully elucidated. In this study, we used an exon array to identify novel splice variants associated with cardiac hypertrophy.Methods and ResultsWe performed genome‐wide exon array analysis and developed a splicing profile in murine hearts with hypertrophy induced by transverse aortic constriction for 8 weeks. Following global analysis of splice variants using the Mouse Exon 1.0 ST Array, we identified 46 spliced genes and narrowed our focus to 1 gene, mitochondrial tumor suppressor 1 (Mtus1), whose splice variants were registered in the NCBI RefSeq database. Notably, one of the splice variants Mtus1A was specifically upregulated, although the total expression of the Mtus1 gene remained unchanged. We showed that Mtus1A was localized in the mitochondria, and its expression level increased with the degree of cardiac hypertrophy. In cultured cardiomyocytes, Mtus1A overexpression reduced phenylephrine‐induced reactive oxygen species production and consequent ERK phosphorylation, resulting in a decrease in both cell size and protein synthesis. In vivo, cardiac‐specific Mtus1A transgenic mice showed left ventricle wall thinning and a reduced hypertrophic response to pressure overload and phenylephrine treatment.ConclusionsWe found that Mtus1 is specifically spliced in hypertrophic hearts and that the Mtus1A variant has an inhibitory effect on cardiac hypertrophy. Mtus1A is, therefore, a possible diagnostic and therapeutic target for cardiac hypertrophy and failure.

Microtubule associated tumor suppressor 1 interacts with mitofusins to regulate mitochondrial morphology in endothelial cells

“…Meanwhile, other studies found that MTUS1 was associated with the microtubule cytoskeleton and localized at the centrosome and mitotic spindle in dividing breast cancer cells (27). It was recently reported that a splice variant of mouse MTUS1a, which is highly homologous to human transcript variant 5, was localized in the mitochondria, whereas MTUS1c, which is highly homologous to human transcript variants 1 and 2 of MTUS1, was colocalized with a-tubulin in cardiomyocytes (15). One possible reason of the distinct cellular localization of MTUS1 is that multiple alternatively spliced transcript variants, which encode different isoforms of MTUS1, are expressed in a cell type-dependent manner.…”

“…MTUS1 deficiency is implicated in multiple types of cancers. It reportedly plays important roles in vascular remodeling (12), adipocyte differentiation (13), lymphocytosis, and cardiac hypertrophy (14,15). We recently reported that MTUS1 transcript variant 5 is the most abundant isoform in ECs, and the loss of MTUS1 resulted in cAMP response element-binding protein (CREB) binding protein (CREBBP)-mediated NF-kB activation in ECs (16).…”

Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology

“…Interestingly, ATIP1 has also been identified as mitochondrial tumor suppressor gene 1 (MTSG1 coded by Mtus1A) whose overexpression suppresses mitochondrial ROS production, ERK activation, and hypertrophy in response to phenylephrine in cardiac myocytes. However, the functional relation of the phenotype with AT 2 R remains unclear (424).…”

Identification of biomarkers, pathways and potential therapeutic targets for heart failure using bioinformatics analysis

“…A previous study reported that CALR (calreticulin) [124], BSCL2 [125], PKD1 [126], TMBIM1 [127], CHST15 [128] [190], SLC2A4 [191], HLA-DOA [192], TAP2 [193], HLA-DPA1 [194], NSMCE2 [195], NDUFA4 [196], HMG20A [197], AMY2B [198] and ACYP2 [199] might be involved in the pathogenesis of diabetics, but these genes might be novel target for HF. Recent evidence indicates that the SIRPA (signal regulatory protein alpha) [200], PFN1 [201], EIF6 [202], AHR (aryl hydrocarbon receptor) [203], RUNX1 [204], IDO1 [205], PDHB (pyruvate dehydrogenase E1 subunit beta) [206], NDUFS1 [207], MTUS1 [208], ZNF418 [209] and MTMR14 [210] are the key biomarkers in cardiac hypertrophy. Previous studies had shown that the expression of CLIC1 [211], ARPC1B [212], FLNA (filamin A) [213], HILPDA (hypoxia inducible lipid droplet associated) [214], RTN3 [215], G0S2 [216], CALU (calumenin) [217], MYDGF (myeloid derived growth factor) [218], LTBR (lymphotoxin beta receptor) [219], GGCX (gamma-glutamyl carboxylase) [220], SAMD1 [221], ACAT1 [222], NNT (nicotinamide nucleotide transhydrogenase) [223] and ATG14 [224] were closely related to the occurrence of atherosclerosis.…”