The Mitochondria-Targeted Methylglyoxal Sequestering Compound, MitoGamide, Is Cardioprotective in the Diabetic Heart

Abstract

Purpose Methylglyoxal, a by-product of glycolysis and a precursor in the formation of advanced glycation end-products, is significantly elevated in the diabetic myocardium. Therefore, we sought to investigate the mitochondria-targeted methylglyoxal scavenger, MitoGamide, in an experimental model of spontaneous diabetic cardiomyopathy. Methods Male 6-week-old Akita or wild type mice received daily oral gavage of MitoGamide or vehicle for 10 weeks. Several morphological and systemic parameters were assessed, as well as cardiac function by echocardiography. Results Akita mice were smaller in size than wild type counterparts in terms of body weight and tibial length. Akita mice exhibited elevated blood glucose and glycated haemoglobin. Total heart and individual ventricles were all smaller in Akita mice. None of the aforementioned parameters was impacted by MitoGamide treatment. Echocardiographic analysis confirmed that cardiac dimensions were smaller in Akita hearts. Diastolic dysfunction was evident in Akita mice, and notably, MitoGamide treatment preferentially improved several of these markers, including e′/a′ ratio and E/e′ ratio. Conclusions Our findings suggest that MitoGamide, a novel mitochondria-targeted approach, offers cardioprotection in experimental diabetes and therefore may offer therapeutic potential for the treatment of cardiomyopathy in patients with diabetes.

Confirmation of the Cardioprotective Effect of MitoGamide in the Diabetic Heart

“…MitoGamide did not change body weight, blood glucose or HbA1c in either Akita or wild-type mice (data not shown). This protection against cardiac dysfunction was the same as that seen in the previous study, validating the effectiveness of MitoGamide [13] and following recent guidelines [25].…”

Icariin Ameliorates Diabetic Cardiomyopathy Through Apelin/Sirt3 Signalling to Improve Mitochondrial Dysfunction

“…Alternatively, the overexpression of the mitochondrial protein Mfn2 restores mitochondrial dysfunction and prevents the development of DCM (Hu et al, 2019). The mitochondrion-targeted methylglyoxal-sequestering compound MitoGamide exhibits cardioprotective effects in an experimental model of DCM (Tate et al, 2019), thereby suggesting that the alleviation of mitochondrial dysfunction may provide a novel therapeutic approach for reversing the development of DCM.…”

ALKBH7 mediates necrosis via rewiring of glyoxal metabolism

“…In seeking links between glyoxal metabolism and necrosis, it is notable that both glycative stress and necrosis are implicated in the pathology of cardiac IR injury ( Almeida et al, 2013 ; Wang et al, 2010 ; Del Re et al, 2019 ). In addition, a mitochondrially targeted MGO scavenging molecule was recently shown to protect the heart against IR injury ( Tate et al, 2019 ). To test the hypothesis that loss of ALKBH7 may protect against IR, perfused hearts from WT and Alkbh7 -/- mice were subjected to IR injury (25 min global ischemia, 60 min reperfusion).…”

“…[29][30][31] In addition, a mitochondrially-targeted MGO scavenging molecule was recently shown to protect the heart against IR injury. 32 To test the hypothesis that loss of ALKBH7 may protect against IR, perfused hearts from WT and Alkbh7 -/mice were subjected to IR injury (25 min. global ischemia, 60 min.…”