Moderate intensity exercise prevents diabetic cardiomyopathy associated contractile dysfunction through restoration of mitochondrial function and connexin 43 levels in db/db mice

Abstract

Aims Although the cardiovascular benefits of exercise are well known, exercise induced effects and mechanisms in prevention of cardiomyopathy are less clear during obesity associated type-2 diabetes. The current study assessed the impact of moderate intensity exercise on diabetic cardiomyopathy by examining cardiac function and structure and mitochondrial function. Methods Obese-diabetic (db/db), and lean control (db/+) mice, were subjected to a 5 week, 300m run on a tread-mill for 5 days/ week at the speeds of 10-11 m/min. Various physiological parameters were recorded and the heart function was evaluated with M-mode echocardiography. Contraction parameters and calcium transits were examined on isolated cardiomyocytes. At the molecular level: connexin 43 and 37 (Cx43 and 37) levels, mitochondrial biogenesis regulators: Mfn2 and Drp-1 levels, mitochondrial trans-membrane potential and cytochrome c leakage were assessed through western blotting immunohistochemistry and flow cytometry. Ability of exercise to reverse oxygen consumption rate (OCR), tissue ATP levels, and cardiac fibrosis were also determined. Results The exercise regimen was able to prevent diabetic cardiac functional deficiencies: ejection fraction (EF) and fractional shortening (FS). Improvements in contraction velocity and contraction maximum were noted with the isolated cardiomyocytes. Restoration of interstitial and micro-vessels associated Cx43 levels and improved gap junction intercellular communication (GJIC) were observed. The decline in the Mfn2/Drp-1 ratio in the db/db mice hearts was prevented after exercise. The exercise regimen further attenuated transmembrane potential decline and cytochrome c leakage. These corrections further led to improvements in OCR and tissue ATP levels and reduction in cardiac fibrosis. Conclusions Moderate intensity exercise produced significant cardiovascular benefits by improving mitochondrial function through restoration of Cx43 networks and mitochondrial trans-membrane potential and prevention of excessive mitochondrial fission.

The effect of endurance training with crocin consumption on the levels of MFN2 and DRP1 gene expression and glucose and insulin indices in the muscle tissue of diabetic rats

“…However, exercise training, by improving insulin sensitivity in the cells, led to a significant decrease in insulin resistance and glucose levels in rats. Moreover, it has recently been shown that exercise inhibits the reduction of the Mfn2/Drp1 ratio in the heart tissue of db/db mice and also reduces cytochrome c leakage (Veeranki et al, 2016). Other studies have also shown that exercise can reduce the expression of Drp1 and increase the expression of Mfn1 and Mfn2 (Fealy, Mulya, Lai, & Kirwan, 2014).…”

“…Other studies have also shown that exercise can reduce the expression of Drp1 and increase the expression of Mfn1 and Mfn2 (Fealy, Mulya, Lai, & Kirwan, 2014). Moreover, it has recently been shown that exercise inhibits the reduction of the Mfn2/Drp1 ratio in the heart tissue of db/db mice and also reduces cytochrome c leakage (Veeranki et al, 2016).…”

Mitochondrial fusion promoter restores mitochondrial dynamics balance and ameliorates diabetic cardiomyopathy in an optic atrophy 1‐dependent way

“…Interestingly, although imbalanced mitochondrial dynamics such as inhibited mitochondrial fusion or excessive mitochondrial fission is common in the hearts at different diabetic conditions, the fission/fusion proteins seem to be differently affected. It has been showed that Drp1 was significantly elevated in the hearts of type 2 diabetic d b /d b mice, whereas reduced protein expression of Mfn1 was observed in cardiac tissues from type 2 diabetic patients . The differences might be due to the differential microenvironment enveloping cardiac myocytes at different diabetic conditions.…”

Altered mitochondrial metabolism in the insulin‐resistant heart

“…250 Similarly, in a separate study 5 weeks of MIT on a treadmill lowered fibrosis and improved ATP levels in the hearts of db/db mice at 4 months of age, alongside improved oxygen consumption rates and improved contractile function in isolated cardiomyocytes. 251 In addition to effects on mitochondrial content and respiratory capacity, exercise may also influence mitochondrial dynamics, with decreased expression of DRP1 relative to that of the mitochondrial fusion factor Mfn1 seen following exercise in db/db mice. 251 The protective effects of exercise may be more limited in the older diabetic heart, however.…”

“…251 In addition to effects on mitochondrial content and respiratory capacity, exercise may also influence mitochondrial dynamics, with decreased expression of DRP1 relative to that of the mitochondrial fusion factor Mfn1 seen following exercise in db/db mice. 251 The protective effects of exercise may be more limited in the older diabetic heart, however. In 8-month-old db/db mice, 3 weeks of endurance training resulted in increased myocardial expression of PGC-1α alongside increased mtDNA density, but decreased ETS complex expression and increased mitochondrial fission, which the authors attributed to increased oxidative stress following exercise in older diabetic hearts.…”