CMTM3 deficiency induces cardiac hypertrophy by regulating MAPK/ERK signaling.

OBJECTIVES: Cardiac hypertrophy is the heart's compensatory response stimulated by various pathophysiological factors. However, prolonged cardiac hypertrophy poses a significant risk of progression to heart failure, lethal arrhythmias, and even sudden cardiac death. For this reason, it is crucial to effectively prevent the occurrence and development of cardiac hypertrophy. CMTM is a superfamily of human chemotaxis, which is involved in immune response and tumorigenesis. CMTM3 expressed widely in tissues, including the heart, but its cardiac function remains unclear. This research aims to explore the effect and mechanism of CMTM3 in the development of cardiac hypertrophy. METHODS AND RESULTS: We generated a Cmtm3 knockout mouse model (Cmtm3-/-) as the loss-of-function approach. CMTM3 deficiency induced cardiac hypertrophy and further exacerbated hypertrophy and cardiac dysfunction stimulated by Angiotensin Ⅱ infusion. In Ang Ⅱ-infusion stimulated hypertrophic hearts and phenylephrine-induced hypertrophic neonatal cardiomyocytes, CMTM3 expression significantly increased. However, adenovirus-mediated overexpression of CMTM3 inhibited the hypertrophy of rat neonatal cardiomyocytes induced by PE stimulation. In terms of mechanism, RNA-seq data revealed that Cmtm3 knockout-induced cardiac hypertrophy was related to MAPK/ERK activation. In vitro, CMTM3 overexpression significantly inhibited the increased phosphorylation of p38 and ERK induced by PE stimulation. CONCLUSIONS: CMTM3 deficiency induces cardiac hypertrophy and aggravates hypertrophy and impaired cardiac function stimulated by angiotensin Ⅱ infusion. The expression of CMTM3 increases during cardiac hypertrophy, and the increased CMTM3 can inhibit further hypertrophy of cardiomyocytes by inhibiting MAPK signaling. Thus, CMTM3 plays a negative regulatory effect in the occurrence and development of cardiac hypertrophy.

Programmed cell death 5 improves skeletal muscle insulin resistance by inhibiting IRS-1 ubiquitination through stabilization of MDM2.

AIMS: Insulin resistance is defined as the decreased sensitivity of tissues and organs to insulin and it is the main pathological basis of metabolic syndrome. PDCD5 is widely expressed in tissues including skeletal muscle and liver, but its exact function and the role in insulin resistance has not been studied. The present study is to explore the effect of PDCD5 on insulin resistance in skeletal muscle, the largest target organ of insulin, and its mechanism. MATERIALS AND METHODS: Mice were fed with high-fat diet to establish obesity model. C2C12 myoblasts differentiated into myotubes and then were treated with palmitate to induce insulin resistance. Gain-of-function and loss-of-function experiments were performed by infecting C2C12 with adenovirus containing PDCD5 cDNA or PDCD5 shRNA. KEY FINDINGS: PDCD5 protein was first increased and then decreased in the skeletal muscle from high-fat diet induced obese mice and consistently in palmitate induced insulin resistance C2C12 myotubes. Overexpression of PDCD5 in C2C12 cells did not affect the sensitivity to insulin but inhibited the palmitate induced insulin resistance, while knockdown of PDCD5 aggravated the insulin resistance. Mechanistically, PDCD5 interacted with ubiquitin ligase MDM2; overexpression of PDCD5 decreased MDM2 protein level, inhibited the increased interaction of MDM2 with IRS-1 and the degradation of IRS-1 by palmitate stimulation. SIGNIFICANCE: PDCD5 is upregulated during the early stage of insulin resistance in skeletal muscle. The increased PDCD5 inhibits IRS-1 ubiquitination, increases the stability of IRS-1 by interacting with and degrading MDM2, thus providing a protective effect on insulin resistance in skeletal muscle.