ABC | Volume 111, Nº3, September 2018

Original Article Pinotti et al Fasting/refeeding cycles and myocardial remodeling Arq Bras Cardiol. 2018; 111(3):400-409 to 48 hours of fasting. 25 This result appears to be mediated by hormones, such as leptin that acts regulating appetite and weight gain. A rapid inhibition of ob gene expression in the white adipose tissue occurs in fasting, and this effect can be reversed by refeeding. 25,26 Cardiac hypertrophy, a major pathological process involved in cardiac remodeling, initially serves as a compensatory mechanism to preserve cardiac output. 27 Cardiac remodeling may be regarded as a first step in the sequence of adaptive responses of the heart to stress caused by a large number of physiological and pathological conditions, such as changes in volume and pressure loads and/or metabolic alterations. 28 Current study revealed that fasting/refeeding induced cardiac atrophy visualized by reduced total heart and left ventricle, as well as in the LVW/FBW. A decrease in left ventricle weight relative to body weight is very common in small animals submitted to food restriction 22 and fasting/refeeding. 29 Inhibition of myocardial protein synthesis and reduction in average protein half-lives are possible explanations for reduced cardiac mass under starvation. 30 Protein synthesis, an anabolic process, is required for cardiac hypertrophy. Two major pathways regulating protein synthesis are inhibited by AMPK, a primary regulator of metabolic pathways, which plays an essential role in a wide variety of cellular processes to protect against cardiac hypertrophy. 31 Therefore, cardiac atrophy could be regulated by the common signaling pathway of AMPK in the hypothalamus. In the ultrastructural analysis, food restriction caused focal morphological damage in most papillary muscle fibers. The same alterations were less intense in the intermittent refeeding condition. Intermittent refeeding seems to aid in the attenuation of the mechanisms responsible for this damage and seems to act by enhancing protein anabolism and retarding protein degradation. Recent findings suggest that the beneficial effects of refeeding result from a reduction in oxidative injury and an increase in cellular stress resistance. 2,32 One possible mechanism for our result may be linked to the expression of atrogin-1, an E3 ubiquitin ligase also known as muscle atrophy F-box (MAFbx). E3-ligases are part of the ubiquitin proteasome pathway utilized for protein degradation during muscle atrophy. The literature has shown that atrogin-1/MAFbx expression results in muscle atrophy during catabolic condition. 33 In cardiac muscle, atrogin-1/MAFbx expression increases during heart failure and pressure overload. 33,34 The isolated papillary muscle analysis showed that food restriction promotes cardiac dysfunction, but refeeding condition prevents the state. These stimuli provide evidence that the improvement of myocardial function assigned to fasting/refeeding cycles was related to changes in intracellular Ca 2+ handling, mainly in the recapture and/or extrusion of Figure 3 – Effects of isoproterenol stimulation on myocardial function in papillary muscles from control (C = black bars), animals with food restriction of 50% (R 50  = gray bars) and animals with alternation between food restriction of 50% and refeeding (RF = white bars). Isoproterenol stimulation experiment: 7 animals each group. Isometric parameters: A: DT (peak developed tension normalized per cross-sectional area); B: +dT/dt (peak isometric tension development rate normalized per cross‑sectional area); C: -dT/dt, g/mm 2 /s (maximum tension decline rate normalized per cross-sectional area). Isotonic parameters: D: PS (percentage of shortening); E: -dL/dt (maximum shortening velocity at L max ); F: +dL/dt (maximum relaxation velocity at L max ). L max : muscle length at peak DT. Values are means ± SD; * significant at p < 0.05 vs. C; †  p < 0.05 vs. R 50 .Repeated measures two-way ANOVA and post hoc Tukey’s test. Source: Research team. 10.0 7.5 5.0 2.5 0.0 basal 0.01 0.1 1 Isoproterenol (µM) basal 0.01 0.1 1 Isoproterenol (µM) basal 0.01 0.1 1 Isoproterenol (µM) basal 0.01 0.1 1 Isoproterenol (µM) basal 0.01 0.1 1 Isoproterenol (µM) basal 0.01 0.1 1 Isoproterenol (µM) DT (g/mm 2 ) +dT/dt (g/mm 2 /s) +dL/dT (ML/s) –dT/dt (g/mm 2 /s) –dL/dT (ML/s) 200 150 100 50 0 60 30 45 15 0 PS (%) 30 20 10 0 4 3 2 1 0 6.0 4.5 3.0 1.5 0.0 † † * * † * * * † *† † C R 50 RF A B D E F C 405