High‐fat diet affects skeletal muscle mitochondria comparable to pressure overload‐induced heart failure

Diabetes mellitus is a systemic metabolic disorder associated with mitochondrial dysfunction, with mitochondrial permeability transition (MPT) pore opening being recognized as one of its pathogenic mechanisms. Alisporivir has been recently identified as a non-immunosuppressive analogue of the MPT pore blocker cyclosporin A and has broad therapeutic potential. The purpose of the present work was to study the effect of alisporivir (2.5 mg/kg/day i.p.) on the ultrastructure and functions of the skeletal muscle mitochondria of mice with diabetes mellitus induced by a high-fat diet combined with streptozotocin injections. The glucose tolerance tests indicated that alisporivir increased the rate of glucose utilization in diabetic mice. An electron microscopy analysis showed that alisporivir prevented diabetes-induced changes in the ultrastructure and content of the mitochondria in myocytes. In diabetes, the ADP-stimulated respiration, respiratory control, and ADP/O ratios and the level of ATP synthase in the mitochondria decreased, whereas alisporivir treatment restored these indicators. Alisporivir eliminated diabetes-induced increases in mitochondrial lipid peroxidation products. Diabetic mice showed decreased mRNA levels of Atp5f1a, Ant1, and Ppif and increased levels of Ant2 in the skeletal muscles. The skeletal muscle mitochondria of diabetic animals were sensitized to the MPT pore opening. Alisporivir normalized the expression level of Ant2 and mitochondrial susceptibility to the MPT pore opening. In parallel, the levels of Mfn2 and Drp1 also returned to control values, suggesting a normalization of mitochondrial dynamics. These findings suggest that the targeting of the MPT pore opening by alisporivir is a therapeutic approach to prevent the development of mitochondrial dysfunction and associated oxidative stress in the skeletal muscles in diabetes.

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3,5-Diiodo-L-Thyronine Affects Structural and Metabolic Features of Skeletal Muscle Mitochondria in High-Fat-Diet Fed Rats Producing a Co-adaptation to the Glycolytic Fiber Phenotype

Frontiers in Physiology ◽

10.3389/fphys.2018.00194 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 6

Author(s):

Elena Silvestri ◽

Federica Cioffi ◽

Rita De Matteis ◽

Rosalba Senese ◽

Pieter de Lange ◽

...

Keyword(s):

Skeletal Muscle ◽

High Fat Diet ◽

High Fat ◽

Muscle Mitochondria ◽

Skeletal Muscle Mitochondria

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Caloric Restriction Followed by High Fat Feeding Predisposes to Oxidative Stress in Skeletal Muscle Mitochondria

Hormone and Metabolic Research ◽

10.1055/s-0033-1351280 ◽

2013 ◽

Vol 45 (12) ◽

pp. 874-879 ◽

Cited By ~ 2

Author(s):

R. Crescenzo ◽

F. Bianco ◽

P. Coppola ◽

A. Mazzoli ◽

G. Liverini ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Caloric Restriction ◽

High Fat ◽

Muscle Mitochondria ◽

Skeletal Muscle Mitochondria ◽

Fat Feeding

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A high-fat diet increases adiposity but maintains mitochondrial oxidative enzymes without affecting development of heart failure with pressure overload

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00599.2009 ◽

2009 ◽

Vol 297 (5) ◽

pp. H1585-H1593 ◽

Cited By ~ 34

Author(s):

David J. Chess ◽

Ramzi J. Khairallah ◽

Karen M. O'Shea ◽

Wenhong Xu ◽

William C. Stanley

Keyword(s):

Heart Failure ◽

Fatty Acid ◽

Cardiac Hypertrophy ◽

High Fat Diet ◽

Citrate Synthase ◽

Pressure Overload ◽

Left Ventricular ◽

Oxidative Enzymes ◽

High Fat ◽

Low Fat Diet

A high-fat diet can increase adiposity, leptin secretion, and plasma fatty acid concentration. In hypertension, this scenario may accelerate cardiac hypertrophy and development of heart failure but could be protective by activating peroxisome proliferator-activated receptors and expression of mitochondrial oxidative enzymes. We assessed the effects of a high-fat diet on the development of left ventricular hypertrophy, remodeling, contractile dysfunction, and the activity of mitochondrial oxidative enzymes. Mice ( n = 10–12/group) underwent transverse aortic constriction (TAC) or sham surgery and were fed either a low-fat diet (10% of energy intake as fat) or a high-fat diet (45% fat) for 6 wk. The high-fat diet increased adipose tissue mass and plasma leptin and insulin. Left ventricular mass and chamber size were unaffected by diet in sham animals. TAC increased left ventricular mass (∼70%) and end-systolic and end-diastolic areas (∼100% and ∼45%, respectively) to the same extent in both dietary groups. The high-fat diet increased plasma free fatty acid concentration and prevented the decline in the activity of the mitochondrial enzymes medium chain acyl-coenzyme A dehydrogenase (MCAD) and citrate synthase that was observed with TAC animals on a low-fat diet. In conclusion, a high-fat diet did not worsen cardiac hypertrophy or left ventricular chamber enlargement despite increases in fat mass and insulin and leptin concentrations. Furthermore, a high-fat diet preserved MCAD and citrate synthase activities during pressure overload, suggesting that it may help maintain mitochondrial oxidative capacity in failing myocardium.

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Abstract 2834: A Short-Term High Fat Diet Impairs Cardiac High Energy Phosphate Metabolism, Exercise Capacity and Cognitive Function

Circulation ◽

10.1161/circ.118.suppl_18.s_784-a ◽

2008 ◽

Vol 118 (suppl_18) ◽

Author(s):

Cameron J Holloway ◽

Lindsay M Edwards ◽

Yaso Emmanuel ◽

Lowri Cochlin ◽

Damian J Tyler ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Cognitive Function ◽

Exercise Capacity ◽

High Fat Diet ◽

Calorie Intake ◽

High Fat ◽

Short Term ◽

Heart Failure Patients ◽

Plasma Ffas

Background: Heart failure patients have low cardiac phosphocreatine/ATP (PCr/ATP) ratios, abnormal exercise tolerance and impaired cognitive function, which may be related to elevated circulating free fatty acids (FFAs). We tested whether briefly raising plasma FFAs, using diet, causes abnormalities in heart, brain and skeletal muscle in healthy subjects Methods and Results: Healthy males (n = 16, age 22 ± 1 years), recruited from the University of Oxford, were randomised to five days of a high fat diet containing 75 ± 1% of calorie intake through fat consumption, or an isocaloric control diet, providing 23 ± 1% of calorie intake as fat. In a cross-over design, subjects undertook the alternate diet after a two week wash out period. Cardiac 31 P magnetic resonance (MR) spectroscopy and MR imaging, echocardiography, exhaustive cycling for 1 h, and CDR computerised cognitive tests were used to assess cardiac PCr/ATP, cardiac function, exercise capacity and cognitive function, respectively, before and after the diets. Subjects on the HFD had a two-fold elevation in plasma FFAs, 12% lower cardiac PCr/ATP with no change in cardiac function, and a 12% lower maximal exercise performance (see Figure ). They also had impaired attention and speed (2.2 vs. 1.9 s, p < 0.001, and 1.10 vs. 1.05 s, respectively, p < 0.01) Discussion: We have shown a short term, high fat diet raised plasma FFA concentrations, impaired myocardial energetics, exercise capacity and cognition. Therefore high plasma FFAs may be detrimental for heart, skeletal muscle and brain in normal subjects and suggests a potential mechanism of impairment in heart failure patients.

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