Fate of isolated adult cardiomyocytes undergoing starvation-induced autophagic degeneration

Takemura, Genzou; Maruyama, Rumi; Goto, Kazuko; Kanamori, Hiromitsu; Tsujimoto, Akiko; Minatoguchi, Shinya; Fujiwara, Hisayoshi

doi:10.4161/auto.5.1.7206

Cited by 10 publications

(8 citation statements)

References 4 publications

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“…2,3 More recently, we extended our study to adult hearts in vivo. 4 In that study, we starved adult GFP-LC3 transgenic mice for up to 3 days and observed the development of autophagy in the heart while using echocardiography and cardiac catheterization to assess cardiac function. Although starvation for 3 days does not affect cardiac function in the mice, morphological and biochemical findings indicate that autophagy is strongly induced in the cardiomyocytes.…”

Section: Autophagy Is Critical For Maintenance Of Cardiac Function During Starvation In the Adultmentioning

confidence: 99%

Autophagy maintains cardiac function in the starved adult

Takemura

Kanamori²,

Goto³

et al. 2009

Autophagy

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To examine the functional significance and detailed morphological characteristics of starvation-induced autophagy in the adult heart, we starved green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice for up to 3 days. Electron microscopy revealed that, after as little as 12 hours of starvation, round and homogenously electron-dense lipid droplet-like vacuoles appeared in cardiomyocytes. These were determined to be lysosomes based on cathepsin D immunopositivity and acid phosphatase activity. The number of these lysosomes increased with starvation time, and typical autolysosomes with intracellular organelles destined for degradation appeared and increased in number at later times during the starvation period. Myocardial expression of the autophagy-related proteins LC3-II, cathepsin D and ubiquitin increased, while myocardial ATP content decreased, as the starvation interval proceeded. Treatment with bafilomycin A(1), an autophagy inhibitor, did not affect cardiac function in normally fed mice, but it significantly depressed cardiac function and caused significant left ventricular dilatation in the mice starved for 3 days. Cardiomyocytes from starved mice treated with bafilomycin A(1) showed marked accumulation of lysosomes, and the myocardial amino acid content, which increased during starvation in normally fed mice, as well as the myocardial ATP content, were severely reduced, which likely contributed to the cardiac dysfunction. The present findings suggest autophagy plays a critical role in the maintenance of cardiac function during starvation in the adult.

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Section: Autophagy Is Critical For Maintenance Of Cardiac Function During Starvation In the Adultmentioning

confidence: 99%

Autophagy maintains cardiac function in the starved adult

Takemura

Kanamori²,

Goto³

et al. 2009

Autophagy

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“…Through its activation of autophagy, mTORC1 inhibition is required for postnatal survival before lactation begins 105 and preserves skeletal muscle integrity and function 106 . Similarly, rapamycin promotes survival of nutrient-deprived cardiomyocytes through autophagy activation 107 . We recently demonstrated that mTORC1 is inhibited during cardiomyocyte energy deprivation and ischemia through the inhibition of Rheb 23 .…”

Section: Introductionmentioning

confidence: 99%

Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease

Sciarretta

Volpe

Sadoshima

2014

Circulation Research

375

314

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The protein kinase mTOR (Mammalian or Mechanistic Target of Rapamycin) is an atypical serine/threonine kinase that exerts its main cellular functions by interacting with specific adaptor proteins to form two different multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 regulates protein synthesis, cell growth and proliferation, autophagy, cell metabolism and stress responses, whereas mTORC2 appears to regulate cell survival and polarity. The mTOR pathway plays a key regulatory function in cardiovascular physiology and pathology. However, the majority of the information available about mTOR function in the cardiovascular system is related to the role of mTORC1 in the unstressed and stressed heart. mTORC1 is required for embryonic cardiovascular development and for postnatal maintenance of cardiac structure and function. In addition, mTORC1 is necessary for cardiac adaptation to pressure overload and development of compensatory hypertrophy. However, partial and selective pharmacologic and genetic inhibition of mTORC1 was shown to extend life span in mammals, reduce pathological hypertrophy and heart failure caused by increased load or genetic cardiomyopathies, reduce myocardial damage after acute and chronic myocardial infarction and reduce cardiac derangements caused by metabolic disorders. The optimal therapeutic strategy to target mTORC1 and increase cardioprotection is under deep investigation. This article reviews the information available regarding the effects exerted by mTOR signaling in cardiovascular physiology and pathological states.

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“…In a similar study using two inhibitors of autophagy, 3-methladenine (3-MA) and leupeptin, there was a reduction in viability of control and glucose-starved cells dose-dependently; the two inhibitors of autophagy acted by different mechanisms because 3-MA reduced the number of autophagic vacuoles that were formed, whereas leupeptin increased their number and size, but without subsequent degradation [73]. Rapamycin, an enhancer of autophagy, improved survival of the glucosestarved cells [73]. Hence, it was declared that autophagy played a role in preserving the life of glucose-starved cells.…”

Section: The Role Of Autophagy In Heart: Pi3k Kinasementioning

confidence: 92%

Autophagy and Heart Failure: A Possible Role for Homocysteine

Vacek

Tyagi

et al. 2011

Cell Biochem Biophys

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Autophagy is a process used for intracellular digestion of organelles and proteins and has special relevance to the long-lived cardiomyocytes in heart disease. The pathway for autophagy and all its mediators remain to be elucidated, but involve such proteins as Atg, Beclin-1, LAMP-2, BH3, Bcl2, PI3K Kinase as well as a plethora of others. It is still not entirely clear whether autophagy is destructive or beneficial to the cell; evidence suggests that the answer is case-specific. For instance, autophagy appears to preserve cell life under cases of ischemia in I/R injury, but is detrimental during reperfusion. High levels of homocysteine (Hcy), a sulfur-containing amino acid, have been shown to be an independent risk factor for chronic heart failure. There are several links to induction and repression of autophagy and Hcy; the following connections to Hcy and autophagy have been made: intracellular nitrous oxide production, intracellular calcium production, and reactive oxygen species production. Further work remains to be elucidated concerning the specific mechanisms under which autophagy occurs and possible Hcy-mediated connections. Moreover, the therapeutic implications might be of some promise to patients.

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Fate of isolated adult cardiomyocytes undergoing starvation-induced autophagic degeneration

Cited by 10 publications

References 4 publications

Autophagy maintains cardiac function in the starved adult

Autophagy maintains cardiac function in the starved adult

Mammalian Target of Rapamycin Signaling in Cardiac Physiology and Disease

Autophagy and Heart Failure: A Possible Role for Homocysteine

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