Voluntary Exercise Improves Cardiac Function and Prevents Cardiac Remodeling in a Mouse Model of Dilated Cardiomyopathy

AbstractWe investigated the effects of voluntary exercise after myocardial infarction (MI) on cardiac function, remodeling, and inflammation. Male C57BL/6J mice were divided into the following four groups: sedentary + sham (Sed-Sh), sedentary + MI (Sed-MI), exercise + sham (Ex-Sh), and exercise + MI (Ex-MI). MI induction was performed by ligation of the left coronary artery. Exercise consisting of voluntary wheel running started after the operation and continued for 4 weeks. The Ex-MI mice had significantly increased cardiac function compared with the Sed-MI mice. The Ex-MI mice showed significantly reduced expression levels of tumor necrosis factor-α, interleukin (IL)-1β, IL-6, and IL-10 in the infarcted area of the left ventricle compared with the Sed-MI mice. In the Ex-MI mice, the expression levels of fibrosis-related genes including collagen I and III were decreased compared to the Sed-MI mice, and the expression levels of IL-1β, IL-6, follistatin-like 1, fibroblast growth factor 21, and mitochondrial function-related genes were significantly elevated in skeletal muscle compared with the Sed mice. The plasma levels of IL-6 were also significantly elevated in the Ex-MI group compared with the Sed-MI groups. These findings suggest that voluntary exercise after MI may improve in cardiac remodeling associated with anti-inflammatory effects in the myocardium and myokine production in the skeletal muscles.

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Ifetroban Reduces Coronary Artery Dysfunction in a Mouse Model of Duchenne Muscular Dystrophy

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00180.2021 ◽

2021 ◽

Author(s):

Ray Mitchell ◽

Norman E Frederick ◽

Emily R Holzman ◽

Francesca Agobe ◽

Heather C M Allaway ◽

...

Keyword(s):

Duchenne Muscular Dystrophy ◽

Muscular Dystrophy ◽

Mouse Model ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Coronary Arteries ◽

Oral Treatment ◽

Mdx Mice ◽

Muscarinic Agonist ◽

Therapeutic Implications

Dilated cardiomyopathy contributes to morbidity and mortality in Duchenne Muscular Dystrophy (DMD), an inheritable muscle wasting disease caused by a mutation in the dystrophin gene. Preclinical studies in mouse models of muscular dystrophy have demonstrated reduced cardiomyopathy and improved cardiac function following oral treatment with the potent and selective thromboxane A2/prostanoid receptor (TPr) antagonist, ifetroban. Further, a phase 2 clinical trial (NCT03340675, Cumberland Pharmaceutical) is currently recruiting subjects to determine if ifetroban can improve cardiac function in patients with DMD. Although TPr is a promising therapeutic target for the treatment of dilated cardiomyopathy in DMD, little is known about TPr function in coronary arteries that perfuse blood through the cardiac tissue. In the current study, isolated coronary arteries from young (~3-5 months) and aged (~9-12 months) mdx mice, a widely used mouse model of DMD, and age-matched controls were examined using wire myography. Vasoconstriction to increasing concentrations of TPr agonist U-46619(U4) was enhanced in young mdx mice versus controls. Additionally, young mdx mice displayed a significant attenuation in endothelial cell-mediated vasodilation to increasing concentrations of the muscarinic agonist acetylcholine (ACh). Since TPr activation was enhanced in young mdx mice, U4-mediated vasoconstriction was measured in the absence and presence of ifetroban. Ifetroban reduced U4-mediated vasoconstriction in young mdx and both aged mdx and control mice. Overall, our data demonstrate enhanced coronary arterial vasoconstriction to TPr activation in young mdx mice, a phenotype that could be reversed with ifetroban. These data could have important therapeutic implications for improving cardiovascular function in DMD.

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Nicotinamide Riboside Preserves Cardiac Function in a Mouse Model of Dilated Cardiomyopathy

Circulation ◽

10.1161/circulationaha.116.026099 ◽

2018 ◽

Vol 137 (21) ◽

pp. 2256-2273 ◽

Cited By ~ 76

Author(s):

Nicolas Diguet ◽

Samuel A.J. Trammell ◽

Cynthia Tannous ◽

Robin Deloux ◽

Jérôme Piquereau ◽

...

Keyword(s):

Mouse Model ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Nicotinamide Riboside

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Apelin improves cardiac function mainly through peripheral vasodilation in a mouse model of dilated cardiomyopathy

Peptides ◽

10.1016/j.peptides.2021.170568 ◽

2021 ◽

Vol 142 ◽

pp. 170568

Author(s):

Brahim El Mathari ◽

Pascale Briand ◽

Alain Corbier ◽

Bruno Poirier ◽

Véronique Briand ◽

...

Keyword(s):

Mouse Model ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Peripheral Vasodilation

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Relation between Voluntary Exercise Frequency and Cardiac Function in Dilated Cardiomyopathy Model Mice

Biophysical Journal ◽

10.1016/j.bpj.2017.11.789 ◽

2018 ◽

Vol 114 (3) ◽

pp. 140a

Author(s):

Masami Sugihara ◽

Ryo Kakigi ◽

Takashi Murayama ◽

Takashi Miida ◽

Takashi Sakurai ◽

...

Keyword(s):

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Voluntary Exercise ◽

Exercise Frequency

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Connective tissue growth factor regulates cardiac function and tissue remodeling in a mouse model of dilated cardiomyopathy

Journal of Molecular and Cellular Cardiology ◽

10.1016/j.yjmcc.2015.11.003 ◽

2015 ◽

Vol 89 ◽

pp. 214-222 ◽

Cited By ~ 17

Author(s):

Yevgeniya E. Koshman ◽

Mark D. Sternlicht ◽

Taehoon Kim ◽

Christopher P. O'Hara ◽

Christopher A. Koczor ◽

...

Keyword(s):

Growth Factor ◽

Connective Tissue ◽

Mouse Model ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Connective Tissue Growth Factor ◽

Tissue Remodeling ◽

Tissue Growth

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HUMAN UMBILICAL CORD BLOOD DERIVED MESENCHYMAL STEM CELLS IMPROVE CARDIAC FUNCTION IN CTNTR141W TRANSGENIC MOUSE MODEL OF DILATED CARDIOMYOPATHY THROUGH MULTIPLE MECHANISMS

Journal of the American College of Cardiology ◽

10.1016/s0735-1097(15)60852-x ◽

2015 ◽

Vol 65 (10) ◽

pp. A852

Author(s):

Xuhe Gong ◽

Guogan Wang

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Mouse Model ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Cord Blood ◽

Umbilical Cord Blood ◽

Transgenic Mouse Model ◽

Human Umbilical Cord Blood ◽

Human Umbilical Cord

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The Effects of Frequency of Voluntary Exercise on Cardiac Function in Dilated Cardiomyopathy Model Mice

Biophysical Journal ◽

10.1016/j.bpj.2018.11.1269 ◽

2019 ◽

Vol 116 (3) ◽

pp. 231a

Author(s):

Masami Sugihara ◽

Ryo Kakigi ◽

Takashi Murayama ◽

Takashi Miida ◽

Takashi Sakurai ◽

...

Keyword(s):

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Voluntary Exercise

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Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy

10.21203/rs.2.17804/v3 ◽

2020 ◽

Author(s):

Bo Jin ◽

Haiming Shi ◽

Zhu Jun ◽

Bangwei Wu ◽

Quzhen Geshang

Keyword(s):

Animal Model ◽

Cardiovascular Diseases ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Cardiac Remodeling ◽

Therapeutic Strategy ◽

Volume Fraction ◽

Pathological Process ◽

Cardiac Myosin ◽

Pathological Mechanism

Abstract Background: Autophagy plays a crucial role in the pathological process of cardiovascular diseases. However, little is known about the pathological mechanism underlying autophagy regulation in dilated cardiomyopathy (DCM). Methods: We explored whether up-regulating autophagy could improve cardiac function in mice with experimental DCM through the mTOR-4EBP1 pathway. Animal model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Both up- or down-regulation of autophagy were studied by administration of rapamycin or 3-MA in parallel. Morphology, Western blotting, and echocardiography were applied to confirm the pathological mechanisms. Results: Autophagy was activated and autophagosomes were significantly increased in the rapamycin group. The collagen volume fraction (CVF) was decreased in the rapamycin group compared with the DCM group (9.21 ± 0.82 % vs 14.38 ± 1.24 %, P<0.01). The expression of p-mTOR and p-4EBP1 were significantly decreased in rapamycin-induced autophagy activation, while the levels were increased by down-regulating autophagy with 3-MA. In the rapamycin group, the LVEF and FS were significantly increased compared with the DCM group (54.12 ± 6.48 % vs 45.29 ± 6.68 %, P <0.01; 26.89 ± 4.04 % vs 22.17 ± 2.82 %, P <0.05). As the inhibitor of autophagy, 3-MA aggravated the progress of maladaptive cardiac remodeling and declined cardiac function in DCM mice. Conclusions: The study indicated a possible mechanism for improving cardiac function in mice with experimental DCM by up-regulating autophagy via the mTOR-4EBP1 pathway, which could be a promising therapeutic strategy for DCM.

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Up-regulating autophagy by targeting the mTOR-4EBP1 pathway: a possible mechanism for improving cardiac function in mice with experimental dilated cardiomyopathy

10.21203/rs.2.17804/v1 ◽

2019 ◽

Author(s):

Bo Jin ◽

Haiming Shi ◽

Zhu Jun ◽

Bangwei Wu ◽

Quzhen Geshang

Keyword(s):

Animal Model ◽

Cardiovascular Diseases ◽

Cardiac Function ◽

Dilated Cardiomyopathy ◽

Cardiac Remodeling ◽

Therapeutic Strategy ◽

Volume Fraction ◽

Pathological Process ◽

Cardiac Myosin ◽

Pathological Mechanism

Abstract Background: Autophagy plays a crucial role in the pathological process of cardiovascular diseases. However, little is known about the pathological mechanism underlying autophagy regulation in dilated cardiomyopathy (DCM).Methods: We explored whether up-regulating autophagy could improve cardiac function in mice with experimental DCM through the mTOR-4EBP1 pathway. Animal model of DCM was established in BALB/c mice by immunization with porcine cardiac myosin. Both up- or down-regulation of autophagy were studied by administration of rapamycin or 3-MA in parallel. Morphology, Western blotting, and echocardiography were applied to confirm the pathological mechanisms.Results: Autophagy was activated and autophagosomes were significantly increased in the rapamycin group. The collagen volume fraction (CVF) was decreased in the rapamycin group compared with the DCM group (9.21 ± 0.82 % vs 14.38 ± 1.24 %, P<0.01). The expression of p-mTOR and p-4EBP1 were significantly decreased in rapamycin-induced autophagy activation, while the levels were increased by down-regulating autophagy with 3-MA. In the rapamycin group, the LVEF and FS were significantly increased compared with the DCM group (54.12 ± 6.48 % vs 45.29 ± 6.68 %, P<0.01; 26.89 ± 4.04 % vs 22.17 ± 2.82 %, P<0.05). As the inhibitor of autophagy, 3-MA aggravated the progress of maladaptive cardiac remodeling and declined cardiac function in DCM mice.Conclusions: The study indicated a possible mechanism for improving cardiac function in mice with experimental DCM by up-regulating autophagy via the mTOR-4EBP1 pathway, which could be a promising therapeutic strategy for DCM.

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