Impact of Leucine Supplementation on Exercise Training Induced Anti-Cardiac Remodeling Effect in Heart Failure Mice

Abstract

Leucine supplementation potentiates the effects of aerobic exercise training (AET) on skeletal muscle; however, its potential effects associated with AET on cardiac muscle have not been clarified yet. We tested whether leucine supplementation would potentiate the anti-cardiac remodeling effect of AET in a genetic model of sympathetic hyperactivity-induced heart failure in mice (α2A/α2CARKO). Mice were assigned to five groups: wild type mice treated with placebo and sedentary (WT, n = 11), α2A/α2CARKO treated with placebo and sedentary (KO, n = 9), α2A/α2CARKO treated with leucine and sedentary (KOL, n = 11), α2A/α2CARKO treated with placebo and AET (KOT, n = 12) or α2A/α2CARKO treated with leucine and AET (KOLT, n = 12). AET consisted of four weeks on a treadmill with 60 min sessions (six days/week, 60% of maximal speed) and administration by gavage of leucine (1.35 g/kg/day) or placebo (distilled water). The AET significantly improved exercise capacity, fractional shortening and re-established cardiomyocytes’ diameter and collagen fraction in KOT. Additionally, AET significantly prevented the proteasome hyperactivity, increased misfolded proteins and HSP27 expression. Isolated leucine supplementation displayed no effect on cardiac function and structure (KOL), however, when associated with AET (KOLT), it increased exercise tolerance to a higher degree than isolated AET (KOT) despite no additional effects on AET induced anti-cardiac remodeling. Our results provide evidence for the modest impact of leucine supplementation on cardiac structure and function in exercised heart failure mice. Leucine supplementation potentiated AET effects on exercise tolerance, which might be related to its recognized impact on skeletal muscle.

Aerobic exercise training rescues protein quality control disruption on white skeletal muscle induced by chronic kidney disease in rats

“…In fact, higher activity of pre-existing antioxidant enzymes induced by AET requires less synthesis of HSPs for efficient inhibition of reactive species attack [43,44,46]. The present study in skeletal muscle corroborates the findings demonstrated previously, when AET restored HSPs and misfolded protein levels in cardiac myocytes from an animal model of heart failure [17] and suggests that in some diseases, sustained but insufficient activation of HSPs is reversed by AET when there is improvement in antioxidant defence systems. In our study, a decrease in HSP content post-training differed from what was observed in reticulum resident GRP78, which increased after AET, demonstrating distinct modulation of cellular chaperones.…”

“…Membranes were incubated with an antisoluble oligomer antibody (Biosource International, Camarillo, California, USA) that recognizes misfolded proteins by exposition to hydrophobic sites. Sample loading was normalized by Ponceau staining .…”

“…This results in a more oxidative phenotype and improved skeletal muscle function, exercise capacity and quality of life in patients . Of interest, different protocols of exercise training have been able to prevent the deleterious effects of UPR‐induced proteotoxicity and re‐established the PQC in different animal tissues . Exercise‐induced UPR activation has been observed in skeletal muscles of both animals and humans .…”

The protective role of small heat shock proteins in cardiac diseases: key role in atrial fibrillation

“…Various studies show that gene and protein levels of HSPB1 and HSPB6 are elevated after physical exercise in rat and mouse models. Interestingly, in these studies, HSPB1 and HSPB6 were phosphorylated, resulting in stabilization of myofilaments, restoration of disrupted contractile proteins, and consequently improved contractile function of the heart (Boluyt et al 2006 ; Burniston 2009 ; Campos et al 2012 ; de Moraes et al 2015 ; Rinaldi et al 2006 ; Sakamoto et al 2006 ). Therefore, physical exercise may represent a promising therapeutic therapy to ameliorate the cardiac function and quality of life in patients with AF and maintain normal sinus rhythm after cardioversion, via induction of HSPB levels.…”

Efeito da suplementação alimentar com leucina no colágeno cardíaco e na função ventricular esquerda associada ao uso da doxorrubicina em ratos Wistar

“…Observações feitas em modelos isquêmicos indicam que ocorrem reações de degradação protéica no coração com perda de aminoácidos devido à ativação dos canais iônicos na membrana celular em condições de hipóxia, fato que induz a perda da força de contração cardíaca. Distúrbios nas membranas celulares por atividade de fosfolipases conduzindo a alterações nos canais sódio-dependentes, têm impacto no efluxo de aminoácidos e o aumento dos níveis destes aminoácidos no sangue que ocorre durante a reperfusão tem sido interpretado como resultado de lesões estruturais mediadas pela produção de radicais livres de oxigênio (MARAZZI et al, 2008 Outra estratégia que tem sido usada para controle da fibrose é a prática de exercícios físicos (DE MORAES et al, 2015) os quais têm sido propostos em associação à leucina como estratégia anti-remodelação sob a premissa de que o exercício físico melhore a função ventricular e que a produção de matriz colágena permanece reduzida. Apesar dos conhecidos benefícios do exercício físico para o coração, o aumento da tensão das fibras cardíacas durante a sua prática impõe aos miofibroblastos um cenário de alta tensão mecânica e as fibras de estresse são ativadas.…”