Rapamycin Reverses Elevated mTORC1 Signaling in Lamin                    A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and                    Extends Survival

Ramos, Fresnida J.; Chen, Steven C.; Garelick, Michael G.; Dai, Dao Fu; Liao, Chen Yu; Schreiber, Katherine H.; MacKay, Vivian L.; An, Elroy H.; Strong, Randy; Ladiges, Warren; Rabinovitch, Peter S.; Kaeberlein, Matt; Kennedy, Brian K.

doi:10.1126/scitranslmed.3003802

Cited by 316 publications

(287 citation statements)

References 66 publications

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“…For example, mitigation of protein synthesis by partial inhib ition of mechanistic target of rapamycin (mTOR), by rapamycin or resveratrol, reversed cardiac hyper trophy and impaired cardiac function in aortic banded mice 176 and protected against myocardial infarction induced HF 177 . Likewise, rapamycin improved cardiac function in DCM in Lmna −/− mice 178 . Conversely, full adult knock out of Rptor, which encodes a component of mTOR complex 1, induced DCM without a hypertrophic response in normal and aortic banded mice 179 .…”

Section: Pharmacological Modulation Of Pqcmentioning

confidence: 93%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

141

126

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The worldwide increase in life expectancy gives rise to an increasing prevalence of cardiac diseases, which remain the leading cause of disability and death in the developed world [1][2][3] . Currently, the mechanisms under lying how ageing contributes to the initiation or acceler ation of cardiac diseases are essentially unresolved. Prevailing theories of ageing centre on gradual derail ment of cellular protein homeostasis -proteostasis -either by design (genetically) or by 'wear and tear' (environmentally) 3 . Central to the role of proteostasis derailment as a major factor in ageing is the observation that protein function declines over time.Proteins are the most versatile and complex macro molecules and are involved in the proper functioning of every biological process 4 . After synthesis as a poly peptide chain from the genetic code, proper function of a protein relies heavily on its correct folding into a 3D native state and on various post translational modifi cations, mostly involving the addition of chem ical groups (including phosphate, acetate, and carbo hydrate). Protein maturation, transport, and ultimately breakdown is monitored and supported by various classes of proteins, collectively called 'protein quality control' (PQC) [3][4][5] . Balanced proteostasis, therefore, depends on proper PQC and is crucial for cellular and organismal health 6 . The intricate network making up the PQC involves numerous proteins, of which the main players are the chaperones and their regula tors 4,7-9 (assisting in folding and refolding of proteins) and the pathways that clear irreversibly misfolded and aggregation prone proteins (the ubiquitin-proteasome system [UPS] and autophagy systems) 9-11 . With ageing, the gradual accumulation of misfolded or damaged pro teins, together with concomitant failure of PQC, results in proteotoxic stress and compromised defence against reactive oxygen species (ROS) 10 , a process that is likely to be accelerated in various age related diseases includ ing neurodegenerative diseases 12,13 , type 2 diabetes mel litus 14 , cancer 15 , and cardiac diseases [16][17][18][19][20] . In addition to the accumulation of misfolded proteins, ageing is accompanied by an imbalance in the proteome, as indi cated by lowered expression of chaperone, proteaso mal, ribosomal, and mitochondrial proteins, whereas proteins related to oxidative stress are upregulated 21,22 . Although mild impairment of proteostasis extends lifespan in Caenorhabditis elegans, referred to as hormesis, sustained impairment is accompanied by loss of PQC to neutralize this effect 3,5 . Importantly, evidence indicates that the amount of soluble, aggregate prone protein oligomers, rather than the abundance of pro tein aggregates, correlates with disease severity 23,24 . Therefore, protein aggregates, which contain both misfolded proteins and elevated levels of chaper ones, constitute an adequate PQC response, aimed at sequestering potentially harmful protein oligomers, rather than embodying the ultimate cellular threat 25 . This ...

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Section: Pharmacological Modulation Of Pqcmentioning

confidence: 93%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

141

126

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“…We also recently demonstrated that AKT-mammalian target of rapamycin (mTOR) 4 signaling is activated in hearts of Lmna H222P/H222P mice (9). Activation of mTOR in hearts of mouse models of LMNA cardiomyopathy (Lmna H222P/H222P and Lmna Ϫ/Ϫ mice) leads to impaired productive autophagy, and its reactivation by mTOR inhibition by rapamycin and its analogs ameliorates the disease (9,10). In the current study, we set out to explore pathogenic mechanisms mediated by ERK1/2 activation in the pathogenesis of LMNA cardiomyopathy.…”

mentioning

confidence: 99%

Dual Specificity Phosphatase 4 Mediates Cardiomyopathy Caused by Lamin A/C (LMNA) Gene Mutation

Choi

Muchir

et al. 2012

Journal of Biological Chemistry

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Background: Mutations in LMNA gene cause cardiomyopathy, for which mechanistic insights are lacking. Results: Dusp4 expression is enhanced in hearts with LMNA cardiomyopathy, and its overexpression in mice causes it by activating AKT-mTOR signaling that impairs autophagy. Conclusions: Dusp4 causes cardiac dysfunction and may contribute to the development of LMNA cardiomyopathy. Significance: Revealing pathogenic mechanisms of LMNA cardiomyopathy is essential for the development of mechanismbased therapies.

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“…Further, activation of PI3-kinase leading to Akt/mTOR phosphorylation, has been demonstrated in laminopathic mice. The event downstream of mTOR activation was inhibition of autophagic detoxification in cells, a deleterious effect that could be counteracted in vivo by rapamycin or its analogs, mTOR inhibitors used in several clinical applications [10,11]. …”

Section: Pathogenetic Pathways In Cardiolaminopathiesmentioning

confidence: 99%

“…These pathogenetic pathways are not mutually exclusive; instead they could be recapitulated in a unique mechanism that, starting from failure of mutated lamin A to regulate TGFbeta 2 levels [15], implies TGFbeta 2 increase [16] and TGFbeta2-dependent activation of Erk 1/2 and mTOR leading to fibrosis [7,15] and loss of autophagic detoxification [11]. In this context, elevated TGFbeta 2 and Akt/mTOR activation could also be the cause of reduced lamin A and prelamin A levels [15,17] at the cardiomyocyte nuclear envelope, a condition that favors LINC disorganization [12].…”

Section: Pathogenetic Pathways In Cardiolaminopathiesmentioning

confidence: 99%

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Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

Boriani

Biagini

Ziacchi

et al. 2018

Nucleus

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Lamin A/C gene mutations can be associated with cardiac diseases, usually referred to as ‘cardiolaminopathies’ characterized by arrhythmic disorders and/or left ventricular or biventricular dysfunction up to an overt picture of heart failure. The phenotypic cardiac manifestations of laminopathies are frequently mixed in complex clinical patterns and specifically may include bradyarrhythmias (sinus node disease or atrioventricular blocks), atrial arrhythmias (atrial fibrillation, atrial flutter, atrial standstill), ventricular tachyarrhythmias and heart failure of variable degrees of severity. Family history, physical examination, laboratory findings (specifically serum creatine phosphokinase values) and ECG findings are often important ‘red flags’ in diagnosing a ‘cardiolaminopathy’. Sudden arrhythmic death, thromboembolic events or stroke and severe heart failure requiring heart transplantation are the most dramatic complications of the evolution of cardiolaminopathies and appropriate risk stratification is clinically needed combined with clinical follow-up. Treatment with cardiac electrical implantable devices is indicated in case of bradyarrhythmias (implant of a device with pacemaker functions), risk of life-threatening ventricular tachyarrhythmias (implant of an ICD) or in case of heart failure with wide QRS interval (implant of a device for cardiac resynchronization). New technologies introduced in the last 5 years can help physicians to reduce device-related complications, thanks to the extension of device longevity and availability of leadless pacemakers or defibrillators, to be implanted in appropriately selected patients. An improved knowledge of the complex pathophysiological pathways involved in cardiolaminopathies and in the determinants of their progression to more severe forms will help to improve clinical management and to better target pharmacological and non-pharmacological treatments.

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Rapamycin Reverses Elevated mTORC1 Signaling in Lamin A/C–Deficient Mice, Rescues Cardiac and Skeletal Muscle Function, and Extends Survival

Cited by 316 publications

References 66 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

Dual Specificity Phosphatase 4 Mediates Cardiomyopathy Caused by Lamin A/C (LMNA) Gene Mutation

Cardiolaminopathies from bench to bedside: challenges in clinical decision-making with focus on arrhythmia-related outcomes

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