Ablating the Rab‐GTPase activating protein TBC1D1 predisposes rats to high‐fat diet‐induced cardiomyopathy

Abstract

Key pointsr Although the role of TBC1D1 within the heart remains unknown, expression of TBC1D1 increases in the left ventricle following an acute infarction, suggesting a biological importance within this tissue.r We investigated the mechanistic role of TBC1D1 within the heart, aiming to establish the consequences of attenuating TBC1D1 signalling in the development of diabetic cardiomyopathy, as well as to determine potential sex differences. r TBC1D1 ablation increased plasma membrane fatty acid binding protein content and myocardial palmitate oxidation. r Following high-fat feeding, TBC1D1 ablation dramatically increased fibrosis and induced end-diastolic dysfunction in both male and female rats in the absence of changes in mitochondrial bioenergetics.r Altogether, independent of sex, ablating TBC1D1 predisposes the left ventricle to pathological remodelling following high-fat feeding, and suggests TBC1D1 protects against diabetic cardiomyopathy.Abstract TBC1D1, a Rab-GTPase activating protein, is involved in the regulation of glucose handling and substrate metabolism within skeletal muscle, and is essential for maintaining pancreatic β-cell mass and insulin secretion. However, the function of TBC1D1 within the heart is largely unknown. Therefore, we examined the role of TBC1D1 in the left ventricle and the functional consequence of ablating TBC1D1 on the susceptibility to high-fat diet-induced abnormalities. Since mutations within TBC1D1 (R125W) display stronger associations with clinical parameters in women, we further examined possible sex differences in the predisposition to diabetic cardiomyopathy. In control-fed animals, TBC1D1 ablation did not alter Pierre-Andre Barbeau completed his undergraduate (2015) and Master's (2017) degrees at the University of Guelph, having been supervised by Dr Graham Holloway in the department of Human Health and Nutritional Sciences. His research focuses on the effects of adaptive (omega 3 fatty acids and exercise) and maladaptive (high-fat feeding) paradigms on various aspects of skeletal and cardiac muscle metabolism, with a particular emphasis on mitochondrial bioenergetics. Jacy Houad attended the University of Guelph to complete an undergraduate degree (2013) in Human Kinetics, and a Master's degree (2014) insulin-stimulated glucose uptake, or echocardiogram parameters, but increased accumulation of a plasma membrane fatty acid transporter and the capacity for palmitate oxidation. When challenged with an 8 week high-fat diet, TBC1D1 knockout rats displayed a four-fold increase in fibrosis compared to wild-type animals, and this was associated with diastolic dysfunction, suggesting a predisposition to diet-induced cardiomyopathy. Interestingly, high-fat feeding only induced cardiac hypertrophy in male TBC1D1 knockout animals, implicating a possible sex difference. Mitochondrial respiratory capacity and substrate sensitivity to pyruvate and ADP were not altered by diet or TBC1D1 ablation, nor were markers of oxidative stress, or indices of overt heart failure. Altogethe...

The ABA-LANCL1/2 Hormone-Receptors System Protects H9c2 Cardiomyocytes from Hypoxia-Induced Mitochondrial Injury via an AMPK- and NO-Mediated Mechanism

“…TBC1D1, and its homolog TBC1D4, are key RabGAPs regulating muscle glucose utilization. In murine skeletal muscle, TBC1D1 appears to control exercise endurance [ 31 ], and its ablation is associated with high-fat diet-induced diastolic dysfunction, left ventricular fibrosis and cardiac hypertrophy [ 32 ]. Increased transcription of TBC1D1 was also observed in L6 skeletal myoblasts overexpressing LANCL1 or LANCL2 [ 15 ].…”

RICH1 is a novel key suppressor of isoproterenol‑ or angiotensin II‑induced cardiomyocyte hypertrophy

“…notably, the inhibitory roles of rabGaPs and rasGaPs in cardiac hypertrophy have previously been reported (15)(16)(17)(18). The ablation of the rabGaP TBC1 domain family member 1 results in significant cardiac hypertrophy in male rats and increased myocardial damage after ischemia/reperfusion (15,16). Similarly, depletion of carabin, another rabGaP, can exacerbate cardiac hypertrophy and significantly reduce fractional shortening in mice (17,18).…”

“…GTPase-activating proteins (GaPs) can induce inactivation of small GTPases by inducing GTP hydrolysis (13,14). notably, the inhibitory roles of rabGaPs and rasGaPs in cardiac hypertrophy have previously been reported (15)(16)(17)(18). The ablation of the rabGaP TBC1 domain family member 1 results in significant cardiac hypertrophy in male rats and increased myocardial damage after ischemia/reperfusion (15,16).…”

Pyroptosis: A possible link between obesity‐related inflammation and inflammatory diseases

“…HFD induced obesity leads to the characteristics of T2D, which in turn leads to DCM (Barbeau et al, 2020). DCM is characterized by functional and structural abnormalities, including myocardial dysfunction, myocardial cell death, myocardial fibroblast activation, and metabolic disorders.…”

“…The mechanism of myocardial cell death induced by these cytokines is mainly related to oxidative and/or nitridation injury. Studies have found that specific superoxide inhibitors can completely block cytokine-induced cardiomyocyte death, so inhibiting cardiomyocyte death can effectively intervene in DCM.HFD induced obesity leads to the characteristics of T2D, which in turn leads to DCM(Barbeau et al, 2020). DCM is characterized by functional and structural abnormalities, including myocardial dysfunction, myocardial cell death, myocardial fibroblast activation, and metabolic disorders.…”