Characterisation of the Myocardial Mitochondria Structural and Functional Phenotype in a Murine Model of Diabetic Cardiomyopathy

Abstract

People affected by diabetes are at an increased risk of developing heart failure than their non-diabetic counterparts, attributed in part to a distinct cardiac pathology termed diabetic cardiomyopathy. Mitochondrial dysfunction and excess reactive oxygen species (ROS) have been implicated in a range of diabetic complications and are a common feature of the diabetic heart. In this study, we sought to characterise impairments in mitochondrial structure and function in a recently described experimental mouse model of diabetic cardiomyopathy. Diabetes was induced in 6-week-old male FVB/N mice by the combination of three consecutive-daily injections of low-dose streptozotocin (STZ, each 55 mg/kg i.p.) and high-fat diet (42% fat from lipids) for 26 weeks. At study end, diabetic mice exhibited elevated blood glucose levels and impaired glucose tolerance, together with increases in both body weight gain and fat mass, replicating several aspects of human type 2 diabetes. The myocardial phenotype of diabetic mice included increased myocardial fibrosis and left ventricular (LV) diastolic dysfunction. Elevated LV superoxide levels were also evident. Diabetic mice exhibited a spectrum of LV mitochondrial changes, including decreased mitochondria area, increased levels of mitochondrial complex-III and complex-V protein abundance, and reduced complex-II oxygen consumption. In conclusion, these data suggest that the low-dose STZ-high fat experimental model replicates some of the mitochondrial changes seen in diabetes, and as such, this model may be useful to study treatments that target the mitochondria in diabetes.

Impairment of Mitochondrial Respiration in Metabolic Diseases: An Overview

“…However, since RCR was increased indicating uncoupling, mitochondrial respiration is inefficient and does not result in higher ATP generation [ 28 , 49 ]. In contrast, Parker et al reported a decrease in succinate-linked OXPHOS in diabetic rat hearts [ 50 ]. Similarly, other authors have found that heart mitochondrial respiration is impaired in diabetic rats, presenting reduced NADH-linked OXPHOS, OXPHOS capacity and decreased ET capacity [ 51 , 52 , 53 , 54 ].…”

Mitochondrial-derived Peptide Single-nucleotide Polymorphisms Associated with Cardiovascular Complications in Type 2 Diabetes

“…Mitochondrial dysfunction and oxidative stress are largely involved in the cellular senescence process observed in malignant neoplasms, aging, and different neurodegenerative and cardiovascular diseases [2]. Although heart failure is multi-factorial, some studies have described an increased risk in diabetic patients, even after therapeutic control measures and prophylaxis for coronary artery disease and hypertension [3].…”

“…Previous analyses have shown that the interaction of genetic variants and environmental factors contribute to the increasing status of metabolic syndromes [16,17]. Several lines of evidence have indicated the roles of oxidative stress and mitochondrial dysfunction in the pathogenesis of aging, including age-related metabolic and neurodegenerative diseases [1,3,9,[18][19][20][21]. However, the basic mechanisms underlying the pathogenesis of metabolic syndromes and cardiovascular complications remain largely unknown.…”

The Role of Mitochondrial Abnormalities in Diabetic Cardiomyopathy

“…In addition, the activity of SIRT1, a crucial regulator of FA metabolism, was decreased, confirming its important role in cardiac metabolic adaptations via FAO modulation [ 82 ]. In the later stages, more severe effects of DMC appeared, for instance, STZ-induced DM mice on HFD for 26 weeks had increased myocardial fibrosis and LV diastolic dysfunction, elevated LV superoxide levels, decreased mitochondria area, increased levels of mitochondrial complex III, and complex V protein abundance, while reducing complex II oxygen consumption [ 83 ].…”