Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemia-reperfusion injury

Abstract

(2015) Repetitive stimulation of autophagy-lysosome machinery by intermittent fasting preconditions the myocardium to ischemiareperfusion injury, Autophagy, 11:9, 1537-1560, DOI: 10.1080/15548627.2015 Keywords: autophagy, fasting, ischemia-reperfusion, lysosome, myocardial infarctionAbbreviations: CMA, chaperone-mediated autophagy; CQ, chloroquine; GFP, green fluorescent protein; LAD, left anterior descending; LAMP2, lysosomal-associated membrane protein 2; MOI, multiplicity of infection; NRCMs, neonatal rat ventricular cardiac myocytes; q4D, quaque qutra die/every fourth day; qOD, quaque otra die/every other day; TFEB, transcription factor EB; MAP1LC3B (also abbreviated as LC3), microtubule-associated protein 1 light chain 3, isoform B; TTC, triphenyl tetrazolium chloride; LV, left ventricle; AAR, area at risk; WT, wild type.Autophagy, a lysosomal degradative pathway, is potently stimulated in the myocardium by fasting and is essential for maintaining cardiac function during prolonged starvation. We tested the hypothesis that intermittent fasting protects against myocardial ischemia-reperfusion injury via transcriptional stimulation of the autophagy-lysosome machinery. Adult C57BL/6 mice subjected to 24-h periods of fasting, every other day, for 6 wk were protected from invivo ischemia-reperfusion injury on a fed day, with marked reduction in infarct size in both sexes as compared with nonfasted controls. This protection was lost in mice heterozygous null for Lamp2 (coding for lysosomal-associated membrane protein 2), which demonstrate impaired autophagy in response to fasting with accumulation of autophagosomes and SQSTM1, an autophagy substrate, in the heart. In lamp2 null mice, intermittent fasting provoked progressive left ventricular dilation, systolic dysfunction and hypertrophy; worsening cardiomyocyte autophagosome accumulation and lack of protection to ischemia-reperfusion injury, suggesting that intact autophagy-lysosome machinery is essential for myocardial homeostasis during intermittent fasting and consequent ischemic cardioprotection. Fasting and refeeding cycles resulted in transcriptional induction followed by downregulation of autophagy-lysosome genes in the myocardium. This was coupled with fasting-induced nuclear translocation of TFEB (transcription factor EB), a master regulator of autophagy-lysosome machinery; followed by rapid decline in nuclear TFEB levels with refeeding. Endogenous TFEB was essential for attenuation of hypoxia-reoxygenation-induced cell death by repetitive starvation, in neonatal rat cardiomyocytes, in-vitro. Taken together, these data suggest that TFEBmediated transcriptional priming of the autophagy-lysosome machinery mediates the beneficial effects of fastinginduced autophagy in myocardial ischemia-reperfusion injury.

Impact of intermittent fasting on health and disease processes

“…Post-MI longitudinal echocardiographic analyses showed that left ventricular remodeling and infarct expansion occurred in rats on the ad libitum diet, but not in those on the ADF diet. Similar to rats, ADF protected the mouse heart against Mi-induced damage (Godar et al, 2015). In contrast to wild type mice, ADF did not protect the hearts of mice with impaired autophagy (Lamp2 heterozygous mutant mice).…”

Protective effects of short-term dietary restriction in surgical stress and chemotherapy

“…Activation of autophagy, possibly due to de-repression upon reduced insulin/IGF-1/mTORC1 signaling, is another common theme in protection. For example, in a mouse model of myocardial IRI, alternate day fasting for 6 weeks protected the myocardium through the transcriptional activation of autophagy, resulting in a reduced infarct size (Godar et al, 2015). Autophagy has also been shown to provide organ protection in the context of renal IRI (Jiang et al, 2010), while the mTORC1 repressor Tsc1 confers neuroprotection in a model of acute ischemic stroke by inducing autophagy (Papadakis et al, 2013).…”

Pharmacological Signatures of the Exenatide Nanoparticles Complex Against Myocardial Ischemia Reperfusion Injury

“…Lipid peroxidation, reactive oxygen species (ROS) production, apoptosis, and DNA/RNA injury are reported to be associated with MI/RI [3]. If these factors are not purged, they may ultimately induce a high incidence of chronic heart failure [4][5][6]. Hence an increasing number of cardiologists are interested in the strategies to reduce MI/RI, including medical treatment, surgical intervention, and gene therapy [7][8][9].…”