Absence of TBC1D4/AS160 impairs cardiac substrate metabolism and increases ischemia/reperfusion-induced myocardial damage

Introduction:

Type 2 Diabetes mellitus (T2DM) represents a significant risk factor for the development and the course of heart diseases. In T2DM, cardiac metabolic flexibility, i.e. the switch between carbohydrates and lipids as energy source, is disturbed. The signaling protein TBC1D4/AS160 is a crucial regulator of glucose and fatty acid utilization for energy production in skeletal muscle and adipose tissue. The aim was to investigate the function of TBC1D4 in cardiac substrate metabolism and adaption to myocardial infarction.

Methods:

Tbc1d4-deficient (D4KO) und wild type (WT) mice at 36 weeks of age were subjected to cardiac ischemia via occlusion of the left anterior descending (LAD) coronary artery and subsequent reperfusion (I/R). Cardiac tissue was subsequently analyzed using histological and biochemical approaches, e.g. transcriptome (NGS-RNASeq) and pathway (IPA) analyses.

Results:

D4KO mice showed a marked reduction of insulin-stimulated glucose uptake in the heart, accompanied by reduced glucose transporter GLUT4 abundance. While basal heart function was not affected, three weeks after I/R, D4KO animals exhibited impaired heart function (e.g. end-systolic/-diastolic volume) as well as substantially increased infarction area, co-occurring with decreased left ventricular wall thickness compared to control animals. The unfolded protein response (UPR) was elevated three weeks after reperfusion. Cardiac transcriptome and pathway analyses attributed a role of TBC1D4 in mitochondria-related pathways and extracellular signaling pathways post-I/R.

Conclusions:

TBC1D4 regulates cardiac glucose uptake and cardiac metabolic flexibility. Our results indicate a functional role of TBC1D4 in adaption to myocardial infarction on the level of UPR and cardiac remodeling.