Effect of exercise on passive myocardial stiffness in mice with diastolic dysfunction

Slater, Rebecca; Strom, Joshua; Granzier, Henk

doi:10.1016/j.yjmcc.2017.04.006

Cited by 20 publications

(39 citation statements)

References 48 publications

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“…In murine studies, two different models of myocarditis , a T2DM model , and a chronic volume overload (shunt) model all showed reduced all‐titin phosphorylation. However, a similar murine shunt model showed no change in all‐titin phosphorylation , as was also the case in a murine model of HFpEF . In contrast, all‐titin phosphorylation was significantly increased in left ventricular (LV) samples from mice exposed to TAC or I/R injury (Fig.…”

Section: Phosphorylation Of the Titin Spring In Normal And Failing Hesupporting

confidence: 54%

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Koser¹,

Loescher²,

Linke³

2019

The FEBS Journal

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Titin is a giant elastic protein expressed in the contractile units of striated muscle cells, including the sarcomeres of cardiomyocytes. The last decade has seen enormous progress in our understanding of how titin molecular elasticity is modulated in a dynamic manner to help cardiac sarcomeres adjust to the varying hemodynamic demands on the heart. Crucial events mediating the rapid modulation of cardiac titin stiffness are post‐translational modifications (PTMs) of titin. In this review, we first recollect what is known from earlier and recent work on the molecular mechanisms of titin extensibility and force generation. The main goal then is to provide a comprehensive overview of current insight into the relationship between titin PTMs and cardiomyocyte stiffness, notably the effect of oxidation and phosphorylation of titin spring segments on titin stiffness. A synopsis is given of which type of oxidative titin modification can cause which effect on titin stiffness. A large part of the review then covers the mechanically relevant phosphorylation sites in titin, their location along the elastic segment, and the protein kinases and phosphatases known to target these sites. We also include a detailed coverage of the complex changes in phosphorylation at specific titin residues, which have been reported in both animal models of heart disease and in human heart failure, and their correlation with titin‐based stiffness alterations. Knowledge of the relationship between titin PTMs and titin elasticity can be exploited in the search for therapeutic approaches aimed at softening the pathologically stiffened myocardium in heart failure patients.

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Section: Phosphorylation Of the Titin Spring In Normal And Failing Hesupporting

confidence: 54%

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Koser¹,

Loescher²,

Linke³

2019

The FEBS Journal

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“…A large body of research spanning several decades has shown the safety and efficacy of regular physical activity in improving outcome in heart failure patients regardless of age, sex or ethnicity . Most clinical and experimental studies, however, have evaluated the remodelling of hearts with ischaemic cardiomyopathy .…”

Section: Discussionmentioning

confidence: 99%

“…Several authors and current guidelines recommend physical exercise for patients with stable heart failure to prevent and/or attenuate cardiac remodelling and skeletal muscle changes and improve functional capacity and quality of life . Physical exercise in experimental heart failure attenuated ventricular dilation, cardiac dysfunction, increased passive stiffness, myocyte hypertrophy, myocardial fibrosis, myocyte calcium handling changes and mitochondrial dysfunction . However, as most benefits of exercise have been described in experimental models of myocardial infarction‐induced heart failure, the effects of exercise during sustained LV pressure‐overload remains poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Exercise during transition from compensated left ventricular hypertrophy to heart failure in aortic stenosis rats

Reyes

Gomes

Rosa

et al. 2018

J Cellular Molecular Medi

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We evaluated the influence of aerobic exercise on cardiac remodelling during the transition from compensated left ventricular (LV) hypertrophy to clinical heart failure in aortic stenosis (AS) rats. Eighteen weeks after AS induction, rats were assigned into sedentary (AS) and exercised (AS‐Ex) groups. Results were compared to Sham rats. Exercise was performed on treadmill for 8 weeks. Exercise improved functional capacity. Echocardiogram showed no differences between AS‐Ex and AS groups. After exercise, fractional shortening and ejection fraction were lower in AS‐Ex than Sham. Myocyte diameter and interstitial collagen fraction were higher in AS and AS‐Ex than Sham; however, myocyte diameter was higher in AS‐Ex than AS. Myocardial oxidative stress, evaluated by lipid hydroperoxide concentration, was higher in AS than Sham and was normalized by exercise. Gene expression of the NADPH oxidase subunits NOX2 and NOX4, which participate in ROS generation, did not differ between groups. Activity of the antioxidant enzyme superoxide dismutase was lower in AS and AS‐Ex than Sham and glutathione peroxidase was lower in AS‐Ex than Sham. Total and reduced myocardial glutathione, which is involved in cellular defence against oxidative stress, was lower in AS than Sham and total glutathione was higher in AS‐Ex than AS. The MAPK JNK was higher in AS‐Ex than Sham and AS groups. Phosphorylated P38 was lower in AS‐Ex than AS. Despite improving functional capacity, aerobic exercise does not change LV function in AS rats. Exercise restores myocardial glutathione, reduces oxidative stress, impairs JNK signalling and further induces myocyte hypertrophy.

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“…Mice were perfused with a solution consisting of 4% formaldehyde, with 70 U/mL of heparin in phosphate buffered saline (PBS), after which the diaphragm was removed and stored in 4% formaldehyde in PBS overnight for complete fixation. Diaphragm midcostal strips were gently flattened between glass slides and sarcomere lengths were measured using a He/Ne laser diffraction system 21, 22…”

Section: Methodsmentioning

confidence: 99%

Titin‐based mechanosensing modulates muscle hypertrophy

Pijl

Strom

Conijn

et al. 2018

J cachexia sarcopenia muscle

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BackgroundTitin is an elastic sarcomeric filament that has been proposed to play a key role in mechanosensing and trophicity of muscle. However, evidence for this proposal is scarce due to the lack of appropriate experimental models to directly test the role of titin in mechanosensing.MethodsWe used unilateral diaphragm denervation (UDD) in mice, an in vivo model in which the denervated hemidiaphragm is passively stretched by the contralateral, innervated hemidiaphragm and hypertrophy rapidly occurs.ResultsIn wildtype mice, the denervated hemidiaphragm mass increased 48 ± 3% after 6 days of UDD, due to the addition of both sarcomeres in series and in parallel. To test whether titin stiffness modulates the hypertrophy response, RBM20ΔRRM and TtnΔIAjxn mouse models were used, with decreased and increased titin stiffness, respectively. RBM20ΔRRM mice (reduced stiffness) showed a 20 ± 6% attenuated hypertrophy response, whereas the TtnΔIAjxn mice (increased stiffness) showed an 18 ± 8% exaggerated response after UDD. Thus, muscle hypertrophy scales with titin stiffness. Protein expression analysis revealed that titin‐binding proteins implicated previously in muscle trophicity were induced during UDD, MARP1 & 2, FHL1, and MuRF1.ConclusionsTitin functions as a mechanosensor that regulates muscle trophicity.

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Effect of exercise on passive myocardial stiffness in mice with diastolic dysfunction

Cited by 20 publications

References 48 publications

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Posttranslational modifications of titin from cardiac muscle: how, where, and what for?

Exercise during transition from compensated left ventricular hypertrophy to heart failure in aortic stenosis rats

Titin‐based mechanosensing modulates muscle hypertrophy

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