Preserved Skeletal Muscle Mitochondrial Function, Redox State, Inflammation and Mass in Obese Mice with Chronic Heart Failure

Abstract

Skeletal muscle (SM) mitochondrial dysfunction, oxidative stress, inflammation and muscle mass loss may worsen prognosis in chronic heart failure (CHF). Diet-induced obesity may also cause SM mitochondrial dysfunction as well as oxidative stress and inflammation, but obesity per se may be paradoxically associated with high SM mass and mitochondrial adenosine triphosphate (ATP) production, as well as with enhanced survival in CHF. Methods: We investigated interactions between myocardial infarction(MI)-induced CHF and diet-induced obesity (12-wk 60% vs. standard 10% fat) in modulating gastrocnemius muscle (GM) mitochondrial ATP and tissue superoxide generation, oxidized glutathione (GSSG), cytokines and insulin signalling activation in 10-wk-old mice in the following groups: lean sham-operated, lean CHF (LCHF), obese CHF (ObCHF; all n = 8). The metabolic impact of obesity per se was investigated by pair-feeding ObCHF to standard diet with stabilized excess body weight until sacrifice at wk 8 post-MI. Results: Compared to sham, LCHF had low GM mass, paralleled by low mitochondrial ATP production and high mitochondrial reative oxygen species (ROS) production, pro-oxidative redox state, pro-inflammatory cytokine changes and low insulin signaling (p < 0.05). In contrast, excess body weight in pair-fed ObCHF was associated with high GM mass, preserved mitochondrial ATP and mitochondrial ROS production, unaltered redox state, tissue cytokines and insulin signaling (p = non significant vs. Sham, p < 0.05 vs. LCHF) despite higher superoxide generation from non-mitochondrial sources. Conclusions: CHF disrupts skeletal muscle mitochondrial function in lean rodents with low ATP and high mitochondrial ROS production, associated with tissue pro-inflammatory cytokine profile, low insulin signaling and muscle mass loss. Following CHF onset, obesity per se is associated with high skeletal muscle mass and preserved tissue ATP production, mitochondrial ROS production, redox state, cytokines and insulin signaling. These paradoxical and potentially favorable obesity-associated metabolic patterns could contribute to reported obesity-induced survival advantage in CHF.

PUFA Supplementation and Heart Failure: Effects on Fibrosis and Cardiac Remodeling

“…In all of these processes, the mitochondria are involved and therefore play a fundamental role in HF. In fact, the altered mitochondrial structure, dynamics, and function in HF generate an energetic deficit and oxidative stress [ 2 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ]. In particular, the process known as ROS-induced ROS release is triggered.…”

n-3 PUFA-Enriched Diet Preserves Skeletal Muscle Mitochondrial Function and Redox State and Prevents Muscle Mass Loss in Mice with Chronic Heart Failure

“…Here, we therefore tested the hypothesis that n -3 PUFA isocaloric partial dietary replacement prevents skeletal muscle catabolism and loss of muscle mass in low-ejection fraction rodent CHF, with normalization of mitochondrial dynamics regulators and prevention of mitochondrial dysfunction and tissue pro-oxidative changes. CHF was triggered by coronary artery ligation, resulting in myocardial infarction and decreased left ventricular ejection fraction (LVEF), as previously reported [ 14 ], in 10-weeks-old mice.…”

“…Weight difference between the amount of chow provided at the start and that remaining at the end of each measurement was used to calculate daily energy intake, according to chow caloric content as reported by the manufacturer. Heart failure was induced in 20 randomly chosen animals by permanent left anterior descending (LAD) coronary artery ligation (CHF), as previously described [ 14 ]. The remaining ten animals underwent sham operation (S).…”

“…The remaining ten animals underwent sham operation (S). To further evaluate cardiac function and confirm CHF, 2-D transthoracic echocardiography was performed using a Vevo 770 Ultrasound device (Visualsonics, Bothell, WA, USA) as previously reported [ 14 ], both after surgery and one week before sacrifice. Animals who underwent LAD ligature but whose LVEF was not reduced to <50% were excluded from the study, leaving n = 8 animals/group.…”

“…Statistical analysis —Sample size was decided by a priori power analysis as reported [ 14 ], assuming that expected differences in muscle mass would be comparable in magnitude to those previously observed in the same coronary artery ligation model. Unpaired ANOVA (GraphPad Prism 8.0, USA) was used for multiple group comparison and was followed by post hoc pairwise t-test with Bonferroni’s correction.…”