Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy

Maloyan, Alina; Gulick, James; Glabe, Charles G.; Kayed, Rakez; Robbins, Jeffrey

doi:10.1073/pnas.0609202104

Cited by 75 publications

(80 citation statements)

References 50 publications

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“…Interestingly, exercise induces autophagy in cardiac muscle of mice 170 . In addition, voluntary exercise in a mouse model of desmin related cardiomyopathy reduced protein aggregation and disease progression 171 . Such effects might underlie exercise related reduction in cardiac fibrosis and hypertrophy and improvement of diastolic function, contractile function, and calcium homeostasis 19,168 .…”

Section: Calorific Restriction and Exercisementioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

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: Calorific Restriction and Exercisementioning

confidence: 99%

Proteostasis in cardiac health and disease

Henning

Brundel²

2017

Nat Rev Cardiol

144

126

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“…Dysfunction of the UPS is rapidly gaining recognition as a potentially important mechanism involved in the pathogenesis of a number of cardiac diseases, including heart failure (38,71,88,93,96,101), cardiomyopathies (12,44,71,78), hypertrophy (18,29,54,72), atrophy (2,72), ischemia-reperfusion (41,67), and atherosclerosis (30), providing a strong rationale for further study of specific mechanisms of proteasome impairment and identification of specific targets for therapy. In vitro and animal models have proven highly valuable in assessing effects of various stressors on the UPS and, in some cases, suggesting a causal link between defective protein clearance and disease phenotypes (14,41,46). Translation of these findings to human disease can be greatly strengthened by corroboration of discoveries from experimental model systems using human heart tissue from well-defined patient populations.…”

Section: Introductionmentioning

confidence: 95%

“…In the animal model, proteasome function is severely impaired, as assessed by the in vivo surrogate UPS substrate green fluorescent protein containing a degron sequence to target to UPS, and occurs before detectable gross cardiac pathology or heart failure (14,43). Furthermore, protein aggregation is required for UPS inhibition (44), and reversal of aggregate formation by voluntary exercise prolongs survival in ␣␤-crystallin mutant mice (46). Together, these data strongly support a pathogenic and causal role for defective protein clearance in DRC that may extrapolate more broadly to other cardiomyopathies associated with abnormal protein aggregation.…”

Section: Comparing Human Disease With Experimental Model Systemsmentioning

confidence: 99%

The ubiquitin proteasome system in human cardiomyopathies and heart failure

Day

2013

American Journal of Physiology-Heart and Circulatory Physiology

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“…Increasing autophagy is beneficial in the context of proteotoxic stress in the heart (17) and increasing autophagy via voluntary exercise (47) increased lifespan in CryAB R120G TG mice (45,48). We subjected CryAB R120G to voluntary exercise, which induces autophagy (45,47).…”

Section: Saha-mediated Cardioprotection Correlates With Increased Autmentioning

confidence: 99%

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

McLendon

Ferguson

Osińska

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

106

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Proteinopathy causes cardiac disease, remodeling, and heart failure but the pathological mechanisms remain obscure. Mutated αB-crystallin (CryAB R120G ), when expressed only in cardiomyocytes in transgenic (TG) mice, causes desmin-related cardiomyopathy, a protein conformational disorder. The disease is characterized by the accumulation of toxic misfolded protein species that present as perinuclear aggregates known as aggresomes. Previously, we have used the CryAB R120G model to determine the underlying processes that result in these pathologic accumulations and to explore potential therapeutic windows that might be used to decrease proteotoxicity. We noted that total ventricular protein is hypoacetylated while hyperacetylation of α-tubulin, a substrate of histone deacetylase 6 (HDAC6) occurs. HDAC6 has critical roles in protein trafficking and autophagy, but its function in the heart is obscure. Here, we test the hypothesis that tubulin acetylation is an adaptive process in cardiomyocytes. By modulating HDAC6 levels and/or activity genetically and pharmacologically, we determined the effects of tubulin acetylation on aggregate formation in CryAB R120G cardiomyocytes. Increasing HDAC6 accelerated aggregate formation, whereas siRNA-mediated knockdown or pharmacological inhibition ameliorated the process. HDAC inhibition in vivo induced tubulin hyperacetylation in CryAB R120G TG hearts, which prevented aggregate formation and significantly improved cardiac function. HDAC6 inhibition also increased autophagic flux in cardiomyocytes, and increased autophagy in the diseased heart correlated with increased tubulin acetylation, suggesting that autophagy induction might underlie the observed cardioprotection. Taken together, our data suggest a mechanistic link between tubulin hyperacetylation and autophagy induction and points to HDAC6 as a viable therapeutic target in cardiovascular disease.P roteotoxicity is an important yet understudied mechanism in cardiac pathobiology (1), as maintaining tight control of protein homeostasis is critical for proper cell function. This is especially important in the unique context of the heart, as it is under constant mechanical and oxidative stress, and cardiomyocytes appear to be largely postmitotic soon after birth and are unable to readily regenerate (2, 3). Cellular stress events, including normal physiologic stimuli, can lead to altered cardiomyocyte function if the pathways of protein quality control (PQC) are compromised. Pathological cardiac stress, including pressure overload-induced hypertrophy and ischemia-reperfusion (I/R) injury, can alter protein degradation pathways (4-6). Our laboratory has developed a model of cardiac proteotoxicity based upon transgenically mediated cardiomyocyte expression of a mutated αB-crystallin (CryAB R120G ), which causes desminrelated cardiomyopathy in humans (7-9).CryAB is a molecular chaperone for desmin, an intermediate filament protein expressed in myocytes. Desmin is a crucial cardiomyocyte protein with vital signaling and structural ro...

show abstract

Exercise reverses preamyloid oligomer and prolongs survival in αB-crystallin-based desmin-related cardiomyopathy

Cited by 75 publications

References 50 publications

Proteostasis in cardiac health and disease

Proteostasis in cardiac health and disease

The ubiquitin proteasome system in human cardiomyopathies and heart failure

Tubulin hyperacetylation is adaptive in cardiac proteotoxicity by promoting autophagy

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