Myofilament modulation of contraction

Biesiadecki, Brandon J.

doi:10.1016/j.abb.2016.05.003

Cited by 4 publications

(4 citation statements)

References 15 publications

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“…On the other hand, post-translational modifications, both oxidative and phosphorylative, may play a more important role in conferring the benefits of SS-31 treatment. In cardiac muscle, the state of post-translational modifications of myofilament proteins are crucial to the regulation of contractile and relaxation behaviors, as shown in the pathophysiology of heart failure ( Biesiadecki, 2016 ; Hamdani et al, 2013a ; Ramirez-Correa et al, 2014 ). In particular, phosphorylation of myofilament proteins is a key modulator of diastolic function of the heart ( Hamdani et al, 2013a ; Hamdani et al, 2013b ; Rosas et al, 2015 ).…”

Section: Discussionmentioning

confidence: 99%

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Chiao

Zhang

Sweetwyne

et al. 2020

eLife

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Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. These results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets for cardiac aging.

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Section: Discussionmentioning

confidence: 99%

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Chiao

Zhang

Sweetwyne

et al. 2020

eLife

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“…On the other hand, post-translational modifications, both oxidative and phosphorylative, may play a more important role in conferring the benefits of SS-31 treatment. In cardiac muscle, the state of post-translational modifications of myofilament proteins are crucial to the regulation of contractile and relaxation behaviors, as shown in the pathophysiology of heart failure [42][43][44] . In particular, phosphorylation of myofilament proteins is a key modulator of diastolic function of the heart 43,45,46 .…”

Section: Normalization Of Proton Leak In Aged Cardiomyocytes Is a Promentioning

confidence: 99%

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Chiao

Zhang

Sweetwyne

et al. 2020

Preprint

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Mitochondrial dysfunction is a hallmark of aging but whether restoration of mitochondrial function can reverse pre-existing age-related diseases is not well-established. Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans, and we show here that 8-week treatment with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit in old mice. Mechanistically, SS-31 treatment normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice; these cellular changes were accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. The improvement in diastolic function was associated with increased phosphorylation at Ser282 of cMyBP-C but was independent of titin isoform shift. SS-31 treatment cannot further improve cardiac function of old mice that express mitochondrial-targeted catalase (mCAT), implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. Late-life viral expression of mCAT produced similar functional benefits in old mice, further indicating that reduction of mitochondrial ROS as a critical mechanism. Despite their similar functional benefits, SS-31 and mCAT differentially regulated cMyBP-C and cTnI phosphorylation, suggesting divergence of mechanisms downstream of mitochondrial ROS reduction. Overall, these results demonstrate that pre-existing cardiac aging phenotypes can be reversed by targeting mitochondrial dysfunction and implicate mitochondrial energetics and redox signaling as therapeutic targets of cardiac aging.

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“…Surprisingly, the MYBPC3 R820W mutation in H5 was not associated with any haploinsufficiency, indicating that this is not an exclusive disease-causing pathway for MYBPC3 mutations. A recent study also failed to identify haploinsufficiency in Maine Coon cats with the A31P mutation (van Dijk et al, 2016 ), indicating that a poison polypeptide mechanism may be involved in HCM due to MYBPC3 mutations in homozygous Ragdoll and Maine Coon cats. HCM not associated with MyBP-C haploinsufficiency has also been noted in some human cases with MYBPC3 mutations (Helms et al, 2014 ).…”

Section: Discussionmentioning

confidence: 99%

Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)

et al. 2017

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Hypertrophic cardiomyopathy (HCM) is the most common single gene inherited cardiomyopathy. In cats (Felix catus) HCM is even more prevalent and affects 16% of the outbred population and up to 26% in pedigree breeds such as Maine Coon and Ragdoll. Homozygous MYBPC3 mutations have been identified in these breeds but the mutations in other cats are unknown. At the clinical and physiological level feline HCM is closely analogous to human HCM but little is known about the primary causative mechanism. Most identified HCM causing mutations are in the genes coding for proteins of the sarcomere. We therefore investigated contractile and regulatory proteins in left ventricular tissue from 25 cats, 18 diagnosed with HCM, including a Ragdoll cat with a homozygous MYBPC3 R820W, and 7 non-HCM cats in comparison with human HCM (from septal myectomy) and donor heart tissue. Myofibrillar protein expression was normal except that we observed 20–44% MyBP-C haploinsufficiency in 5 of the HCM cats. Troponin extracted from 8 HCM and 5 non-HCM cat hearts was incorporated into thin filaments and studied by in vitro motility assay. All HCM cat hearts had a higher (2.06 ± 0.13 fold) Ca2+-sensitivity than non-HCM cats and, in all the HCM cats, Ca2+-sensitivity was not modulated by troponin I phosphorylation. We were able to restore modulation of Ca2+-sensitivity by replacing troponin T with wild-type protein or by adding 100 μM Epigallocatechin 3-gallate (EGCG). These fundamental regulatory characteristics closely mimic those seen in human HCM indicating a common molecular mechanism that is independent of the causative mutation. Thus, the HCM cat is a potentially useful large animal model.

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Myofilament modulation of contraction

Cited by 4 publications

References 15 publications

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice

Investigations into the Sarcomeric Protein and Ca2+-Regulation Abnormalities Underlying Hypertrophic Cardiomyopathy in Cats (Felix catus)

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