The mTOR Signaling Pathway in Myocardial Dysfunction in Type 2 Diabetes Mellitus

Abstract

Purpose of review: T2DM (type 2 diabetes mellitus) is a risk factor for heart failure. The mTOR (mechanistic target of rapamycin) is a key mediator of the insulin signaling pathway. We will discuss the role of mTOR in myocardial dysfunction in T2DM.

Recent findings: In T2DM, chronically activated mTOR induces multiple pathological events, including a negative feedback loop that suppresses IRS (insulin receptor substrate)-1. While short-term treatment with rapamycin, an mTOR inhibitor, is a promising strategy for cardiac diseases such as acute myocardial infarction and cardiac hypertrophy in T2DM, there are many concerns about chronic usage of rapamycin. Two mTOR complexes, mTORC1 and mTORC2, affect many molecules and processes via distinct signaling pathways that regulate cardiomyocyte function and survival. Understanding mechanisms underlying mTOR-mediated pathophysiological features in the heart is essential for developing effective therapies for cardiac diseases in the context of T2DM.

Keywords: Cardiovascular disease; Cell signaling; Diabetes mellitus; Heart failure; Rapamycin; mTOR.

Fig 1.. Signaling pathways of mTOR complex activation and regulation.

AMPK, AMP-dependent protein kinase; DEPTOR, DEP-domain-containing mTOR interacting protein; elF4E, eukaryotic translation initiation factor 4E; ER, endoplasmic reticulum; FKBP12, FK506-binding protein 12kDa; Foxo1/3, forkhead box protein O 1/3; Grb10, growth factor receptor-bound protein 10; GSK-3β, glycogen synthase kinase 3β; IRS-1, insulin receptor substrate 1; mLST8, mammalian lethal with Sec 13 protein 8; mTOR, mechanistic target of rapamycin; mTORC1/2, mTOR complex 1 and 2; PDK1, phosphoinositide-dependent kinase 1; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; PRAS40, proline-rich Akt/PKB substrate 40 kDa; RAPTOR, regulatory associated protein of mTOR; RICTOR, rapamycin-insensitive companion of mTOR; Rheb, Ras homologue enriched in brain; SGK, serum- and glucocorticoid-regulated kinase; SIN1, stress-activated protein kinase-interacting protein; Tel2, telomere maintenance 2; TSC1/2, tuberous sclerosis complex 1 and 2; Tti1, Tel2 interaction protein 1; 4E-BP1, 4E-binding protein 1.