Effects of elamipretide on skeletal muscle in dogs with experimentally induced heart failure

Sabbah, Hani N.; Gupta, Ramesh C.; Singh‐Gupta, Vinita; Zhang, Kefei

doi:10.1002/ehf2.12408

Cited by 24 publications

(26 citation statements)

References 34 publications

(79 reference statements)

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“…Further, we show that SS-31 treatment preserved mitochondrial function in both cardiac and diaphragm muscle from C26 mice by preserving oxidative phosphorylation and preventing proton leak into the mitochondrial matrix. A similar positive influence of SS-31 on cardiac and skeletal muscle in heart failure was recently shown which implicated mitochondrial bioenergetics and redox signaling in the development of muscle dysfunction [31,32]. This is important because increased proton leak can augment oxidant production within the mitochondrial matrix leading to a disruption of redox balance within the muscle tissue [33,34].…”

Section: Discussionmentioning

confidence: 53%

“…These data suggest that the effects to diaphragm and cardiac muscle were the result of tumor growth and SS-31 treatment. Direct targeting of mitochondria with the SS-31 peptide is established to prevent cardiac and respiratory muscle weakness that occurs following a variety of conditions, including ventilator-induced diaphragm dysfunction, heart failure, sepsis and chemotherapyrelated cachexia [15][16][17][18][19]31]. Evidence from these studies indicates that perturbations to mitochondrial function can act as an upstream trigger in the activation of pathways which promote degradation of the muscle contractile apparatus resulting in muscle atrophy and weakness [15][16][17][18][19].…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

et al. 2020

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Cancer cachexia is a syndrome characterized by profound cardiac and diaphragm muscle wasting, which increase the risk of morbidity in cancer patients due to failure of the cardiorespiratory system. In this regard, muscle relies greatly on mitochondria to meet energy requirements for contraction and mitochondrial dysfunction can result in muscle weakness and fatigue. In addition, mitochondria are a major source of reactive oxygen species (ROS) production, which can stimulate increased rates of muscle protein degradation. Therefore, it has been suggested that mitochondrial dysfunction may be an underlying factor that contributes to the pathology of cancer cachexia. To determine if pharmacologically targeting mitochondrial dysfunction via treatment with the mitochondria-targeting peptide SS-31 would prevent cardiorespiratory muscle dysfunction, colon 26 (C26) adenocarcinoma tumor-bearing mice were administered either saline or SS-31 daily (3 mg/kg/day) following inoculation. C26 mice treated with saline demonstrated greater ROS production and mitochondrial uncoupling compared to C26 mice receiving SS-31 in both the heart and diaphragm muscle. In addition, saline-treated C26 mice exhibited a decline in left ventricular function which was significantly rescued in C26 mice treated with SS-31. In the diaphragm, muscle fiber cross-sectional area of C26 mice treated with saline was significantly reduced and force production was impaired compared to C26, SS-31-treated animals. Finally, ventilatory deficits were also attenuated in C26 mice treated with SS-31, compared to saline treatment. These data demonstrate that C26 tumors promote severe cardiac and respiratory myopathy, and that prevention of mitochondrial dysfunction is sufficient to preclude cancer cachexia-induced cardiorespiratory dysfunction. Author contributions AJS, HHS and ARJ designed the study. AJS, BMR, MPW, OK, JY, DDC and DDF performed the experiments and analyzed the data. HHS provided the SS-31. AJS and ARJ wrote the manuscript. All authors reviewed and approved the final version of the manuscript.

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Section: Discussionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 99%

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

et al. 2020

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“…Mitochondrial dysfunction therefore plays a central role in a wide variety of metabolic and cardiac disorders, including heart failure (HF) and BTHS [ 1 , 18 ], the subject of this review. Dysfunctional mitochondria in skeletal muscle has been implicated in HF-associated exercise intolerance [ 19 ] and in skeletal muscle myopathy and exercise intolerance in BTHS [ 20 ].…”

Section: Mitochondrial Bioenergeticsmentioning

confidence: 99%

Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide

Sabbah

2020

Heart Fail Rev

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Barth syndrome (BTHS) is a rare, X-linked recessive, infantile-onset debilitating disorder characterized by early-onset cardiomyopathy, skeletal muscle myopathy, growth delay, and neutropenia, with a worldwide incidence of 1/300,000–400,000 live births. The high mortality rate throughout infancy in BTHS patients is related primarily to progressive cardiomyopathy and a weakened immune system. BTHS is caused by defects in the TAZ gene that encodes tafazzin, a transacylase responsible for the remodeling and maturation of the mitochondrial phospholipid cardiolipin (CL), which is critical to normal mitochondrial structure and function (i.e., ATP generation). A deficiency in tafazzin results in up to a 95% reduction in levels of structurally mature CL. Because the heart is the most metabolically active organ in the body, with the highest mitochondrial content of any tissue, mitochondrial dysfunction plays a key role in the development of heart failure in patients with BTHS. Changes in mitochondrial oxidative phosphorylation reduce the ability of mitochondria to meet the ATP demands of the human heart as well as skeletal muscle, namely ATP synthesis does not match the rate of ATP consumption. The presence of several cardiomyopathic phenotypes have been described in BTHS, including dilated cardiomyopathy, left ventricular noncompaction, either alone or in conjunction with other cardiomyopathic phenotypes, endocardial fibroelastosis, hypertrophic cardiomyopathy, and an apical form of hypertrophic cardiomyopathy, among others, all of which can be directly attributed to the lack of CL synthesis, remodeling, and maturation with subsequent mitochondrial dysfunction. Several mechanisms by which these cardiomyopathic phenotypes exist have been proposed, thereby identifying potential targets for treatment. Dysfunction of the sarcoplasmic reticulum Ca2+-ATPase pump and inflammation potentially triggered by circulating mitochondrial components have been identified. Currently, treatment modalities are aimed at addressing symptomatology of HF in BTHS, but do not address the underlying pathology. One novel therapeutic approach includes elamipretide, which crosses the mitochondrial outer membrane to localize to the inner membrane where it associates with cardiolipin to enhance ATP synthesis in several organs, including the heart. Encouraging clinical results of the use of elamipretide in treating patients with BTHS support the potential use of this drug for management of this rare disease.

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“…Mitochondrial dysfunction can have deleterious consequences for the heart physiology and affects many forms of heart disease [ 5 , 6 ]. Dysfunctional mitochondria in skeletal muscle also impact heart failure and are associated with exercise intolerance [ 7 ].…”

Section: Introductionmentioning

confidence: 99%

Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies

Wasmus¹,

Dudek²

2020

Life

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The heart is the most energy-consuming organ in the human body. In heart failure, the homeostasis of energy supply and demand is endangered by an increase in cardiomyocyte workload, or by an insufficiency in energy-providing processes. Energy metabolism is directly associated with mitochondrial redox homeostasis. The production of toxic reactive oxygen species (ROS) may overwhelm mitochondrial and cellular ROS defense mechanisms in case of heart failure. Mitochondria are essential cell organelles and provide 95% of the required energy in the heart. Metabolic remodeling, changes in mitochondrial structure or function, and alterations in mitochondrial calcium signaling diminish mitochondrial energy provision in many forms of cardiomyopathy. The mitochondrial respiratory chain creates a proton gradient across the inner mitochondrial membrane, which couples respiration with oxidative phosphorylation and the preservation of energy in the chemical bonds of ATP. Akin to other mitochondrial enzymes, the respiratory chain is integrated into the inner mitochondrial membrane. The tight association with the mitochondrial phospholipid cardiolipin (CL) ensures its structural integrity and coordinates enzymatic activity. This review focuses on how changes in mitochondrial CL may be associated with heart failure. Dysfunctional CL has been found in diabetic cardiomyopathy, ischemia reperfusion injury and the aging heart. Barth syndrome (BTHS) is caused by an inherited defect in the biosynthesis of cardiolipin. Moreover, a dysfunctional CL pool causes other types of rare inherited cardiomyopathies, such as Sengers syndrome and Dilated Cardiomyopathy with Ataxia (DCMA). Here we review the impact of cardiolipin deficiency on mitochondrial functions in cellular and animal models. We describe the molecular mechanisms concerning mitochondrial dysfunction as an incitement of cardiomyopathy and discuss potential therapeutic strategies.

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Effects of elamipretide on skeletal muscle in dogs with experimentally induced heart failure

Cited by 24 publications

References 34 publications

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

Pharmacological targeting of mitochondrial function and reactive oxygen species production prevents colon 26 cancer-induced cardiorespiratory muscle weakness

Barth syndrome cardiomyopathy: targeting the mitochondria with elamipretide

Metabolic Alterations Caused by Defective Cardiolipin Remodeling in Inherited Cardiomyopathies

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