Under construction: The dynamic assembly, maintenance, and degradation of the cardiac sarcomere

Martin, Thomas G.; Kirk, Jonathan A.

doi:10.1016/j.yjmcc.2020.08.018

Cited by 68 publications

(55 citation statements)

References 239 publications

(262 reference statements)

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“…Since impairment to PQC mechanisms is a common feature of heart failure 31 , we hypothesized that disrupted removal of misfolded/ dysfunctional sarcomere proteins might underly the observed decrease in F max . With functioning PQC, misfolded proteins are tagged with ubiquitin and then removed through various protein degradation mechanisms 12 . Thus, increased ubiquitin levels may serve as a readout for disrupted protein turnover, where proteins are effectively marked for degradation but fail to be turned over.…”

Section: Resultsmentioning

confidence: 99%

“…Disrupted proteostasis has long been associated with sarcomere structural abnormalities and heart failure 12 , 48 – 50 . However, mechanisms of sarcomere protein turnover and the myofilament functional significance of individual molecular chaperones involved in sarcomere PQC are not known.…”

Section: Discussionmentioning

confidence: 99%

“…The sarcomere is under constant mechanical strain, which predisposes its members to denaturation, and yet must maintain optimal mechanical function for decades in the terminally differentiated adult cardiomyocyte. To preserve function, stress-denatured sarcomere proteins must be refolded or targeted to degradation pathways by molecular chaperones so that new proteins can be incorporated 12 . However, sarcomeric protein quality control (PQC) is frequently impaired in heart failure, leading to toxic aggregation of misfolded/dysfunctional proteins 12 .…”

Section: Introductionmentioning

confidence: 99%

“…To preserve function, stress-denatured sarcomere proteins must be refolded or targeted to degradation pathways by molecular chaperones so that new proteins can be incorporated 12 . However, sarcomeric protein quality control (PQC) is frequently impaired in heart failure, leading to toxic aggregation of misfolded/dysfunctional proteins 12 . An arrested removal of dysfunctional sarcomere proteins in heart failure may thus serve as a plausible mechanism for the observed decrease in F max .…”

Section: Introductionmentioning

confidence: 99%

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Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

et al. 2021

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The association between reduced myofilament force-generating capacity (Fmax) and heart failure (HF) is clear, however the underlying molecular mechanisms are poorly understood. Here, we show impaired Fmax arises from reduced BAG3-mediated sarcomere turnover. Myofilament BAG3 expression decreases in human HF and positively correlates with Fmax. We confirm this relationship using BAG3 haploinsufficient mice, which display reduced Fmax and increased myofilament ubiquitination, suggesting impaired protein turnover. We show cardiac BAG3 operates via chaperone-assisted selective autophagy (CASA), conserved from skeletal muscle, and confirm sarcomeric CASA complex localization is BAG3/proteotoxic stress-dependent. Using mass spectrometry, we characterize the myofilament CASA interactome in the human heart and identify eight clients of BAG3-mediated turnover. To determine if increasing BAG3 expression in HF can restore sarcomere proteostasis/Fmax, HF mice were treated with rAAV9-BAG3. Gene therapy fully rescued Fmax and CASA protein turnover after four weeks. Our findings indicate BAG3-mediated sarcomere turnover is fundamental for myofilament functional maintenance.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

et al. 2021

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“…The current paradigm of cardiac pathophysiology holds that the cardiac sarcomere is the basic contractile unit of the heart 27 , and that sarcomeric dysfunction drives changes in cardiac muscle contractility central to impaired cardiac function 28 . The structure and function of the cardiac sarcomere is regulated by phosphorylation of the myo lament proteins 28,29 .…”

Section: Rest Induced Contractile Function and Phosphorylation Of Sarmentioning

confidence: 99%

Rest Profoundly Protects Against Cardiac Remodeling and Benefits Repair

Martino

Reitz

Alibhai

et al. 2021

Preprint

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Cardiovascular disease is a leading cause of morbidity and mortality worldwide1. Although rest has long been considered beneficial to patients2, remarkably there are no evidence-based experimental models determining how it benefits disease outcomes. Here, we create a novel experimental rest model in mice, whereby light-induced manipulation of the circadian system briefly extends the rest period by 4 hours each morning. We found, in two different cardiovascular disease conditions (cardiac hypertrophy, myocardial infarction), that imposing a short, extended period of rest each day persistently reduces cardiac remodeling, as compared to control mice subjected to only normal periods of rest, supporting the therapeutic benefits of rest to slow functional decompensation in heart disease. Mechanistically, rest reduces hemodynamic stress on the cardiovascular system, imposing changes on myofilament contractile function in the heart independently consistent within each disease phenotype. Molecular analyses reveal attenuation of cardiac remodeling genes, consistent with the benefits on cardiac structure and function. These same cardiac remodeling genes underlie the pathophysiology of many major human cardiovascular conditions, as demonstrated by interrogating open-source transcriptomic data, and thus patients with other conditions may also benefit from a morning rest period in a similar manner. In summary, we report that rest is a key driver of physiology, leading to the development of an entirely new field on the nature of rest, and provide a strong rationale for advancement of rest based therapy for major clinical diseases.

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Post‐translational modifications of vertebrate striated muscle myosin heavy chains

Morales,

Coons,

Koopman

et al. 2024

Cytoskeleton

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Post‐translational modifications (PTMs) play a crucial role in regulating the function of many sarcomeric proteins, including myosin. Myosins comprise a family of motor proteins that play fundamental roles in cell motility in general and muscle contraction in particular. A myosin molecule consists of two myosin heavy chains (MyHCs) and two pairs of myosin light chains (MLCs); two MLCs are associated with the neck region of each MyHC's N‐terminal head domain, while the two MyHC C‐terminal tails form a coiled‐coil that polymerizes with other MyHCs to form the thick filament backbone. Myosin undergoes extensive PTMs, and dysregulation of these PTMs may lead to abnormal muscle function and contribute to the development of myopathies and cardiovascular disorders. Recent studies have uncovered the significance of PTMs in regulating MyHC function and showed how these PTMs may provide additional modulation of contractile processes. Here, we discuss MyHC PTMs that have been biochemically and/or functionally studied in mammals' and rodents' striated muscle. We have identified hotspots or specific regions in three isoforms of myosin (MYH2, MYH6, and MYH7) where the prevalence of PTMs is more frequent and could potentially play a significant role in fine‐tuning the activity of these proteins.

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Under construction: The dynamic assembly, maintenance, and degradation of the cardiac sarcomere

Cited by 68 publications

References 239 publications

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

Cardiomyocyte contractile impairment in heart failure results from reduced BAG3-mediated sarcomeric protein turnover

Rest Profoundly Protects Against Cardiac Remodeling and Benefits Repair

Post‐translational modifications of vertebrate striated muscle myosin heavy chains

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