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Regulation of Skeletal Muscle Reactive Oxygen Species During Exercise
Published in Peter M. Tiidus, Rebecca E. K. MacPherson, Paul J. LeBlanc, Andrea R. Josse, The Routledge Handbook on Biochemistry of Exercise, 2020
Catherine A. Bellissimo, Christopher G.R. Perry
Similar findings have been found in the heart after exercise training. Rodents that engaged in exercise training experienced less cardiac necrosis following experimental induction of myocardial infarction (14). This cardioprotective effect of exercise was not prevented by daily administration of the mitochondrial cardiolipin-targeted compound Bendavia, which prevents increases in mitochondrial ROS. This result suggests that cardiac mitochondrial ROS is not increased during exercise training, or at least that mitochondrial ROS does not mediate the cardioprotective effects of exercise. In contrast, NOX inhibition with apocynin or Vas2870, which inhibits multiple NOX isoforms (4), prevented the cardioprotective effect of exercise such that necrosis was similar to controls after a myocardial infarction. These results add to the lines of evidence outlined earlier that exercise may not increase mitochondrial ROS to a level sufficient to trigger adaptation, whereas NOX may be a more predominant source, as discussed later.
Cardiovascular Disease and Oxidative Stress
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Marco Fernandes, Alisha Patel, Holger Husi
Pathological sources of mitochondrial dysfunction could be targeted using peptides belonging to the Szeto-Schiller (SS) family such as the SS-31(also known as MTP-131 and Bendavia) (Szeto and Birk, 2014). They bind to cardiolipin and prevent its oxidation, thereby enhancing electron transfer within the electron transfer chain (ETC) and diminishing production and ultimately restoring cellular bioenergetics (Birk et al., 2014). Treatment with SS-31 and the SS-20 analogues reduced lipid peroxidation and infarct size in ischemia reperfusion injury (IRI) murine models (Cho et al., 2007). Moreover, SS-31 mitigates release of cytokines in response to treatment with TNF-alpha in skeletal muscle cells using mouse myoblast cell lines such as C2C12 myotubes (Lightfoot et al., 2015).
Mitochondrial Oxidative Stress in Aging and Healthspan
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Direct evidence was shown by the protective effect of mCAT mouse brains against MPTP-induced mitochondrial ROS production and subsequent dopaminergic neuron degeneration in substantia nigra pars compacta.153 In contrast, mice with defective mitochondria are more susceptible to MPTP-induced dopaminergic neuronal cell death. For example, harlequin mice with partial deficiency of apoptosis inducing factor, which is required for maintenance of mitochondrial complex I, display increased susceptibility to MPTP. This is reversed by the antioxidant tempol (SOD-mimetic).153 Another study demonstrated that mitochondrial protective peptide SS31 (Bendavia) protects dopaminergic neurons and preserves striatal dopamine levels in mice treated with MPTP (see section Potential Interventions).154
Omaveloxolone: an activator of Nrf2 for the treatment of Friedreich ataxia
Published in Expert Opinion on Investigational Drugs, 2023
Victoria Profeta, Kellie McIntyre, McKenzie Wells, Courtney Park, David R Lynch
(also known as MTP131, Bendavia, SS-31) is a potential therapy for FRDA, which attempts to alter the pathophysiology of disease by improving mitochondrial function. Elamipretide is a cell-permeable tetrapeptide that binds to cardiolipin in the inner mitochondrial membrane (IMM) [49,50]. Cardiolipin, a distinct phospholipid found in IMM, is crucial for the formation of cristae and is particularly sensitive to peroxidation; oxidation of cardiolipin results in a loss of curvature in the mitochondrial membrane, disrupting the organization of respiratory complexes and reducing affinity for cytochrome c, reducing oxidative phosphorylation, and thus diminishing the available ATP within a cell [49,51]. Elamipretide has shown benefit in cellular and animal models of FRDA [52–54]. Cells with higher energy demands such as the central nervous system (CNS), heart, kidney, and muscle should be more impacted by such events. Elamipretide stabilizes cardiolipin in the IMM to restore the structure of cristae allowing for proper function to resume [51]. At present, there is only a single active trial of Elamipretide in FRDA (for later stage visual loss) with no direct evidence for benefit at present in human FRDA for this investigational agent.
Investigational drugs in phase II clinical trials for acute coronary syndromes
Published in Expert Opinion on Investigational Drugs, 2020
Amit Rout, Ajaypaul Sukhi, Rahul Chaudhary, Kevin P Bliden, Udaya S Tantry, Paul A Gurbel
Cardiolipin is a phospholipid present on the inner mitochondrial membrane. Cardiolipin plays an important role in several mitochondrial biochemical processes and maintenance of inner membrane stability. Loss of cardiolipin from aging or damage by reactive oxygen species leads to cell death [106]. MTP-131(Stealth BioTherapeutics Inc. Newton, MA, USA) is a mitochondria targeting peptide that selectively binds to cardiolipin and preserves its integrity. Reactive oxygen species (ROS) play a significant role in myocardial injury after ACS. MTP-131 reduces ROS levels in cardiomyocyte mitochondria and can reduce reperfusion injury after an ACS event. In animal models, MTP-131 was shown to reduce infarct size in STEMI models and also improved left ventricular ejection fraction [107,108]. EMBRACE STEMI (Evaluation of Myocardial Effects of Bendavia for Reducing Reperfusion Injury in Patients With Acute Coronary Events), a phase II study (NCT01572909), evaluated the safety and efficacy of MTP-131 in patients with STEMI undergoing PCI. The primary endpoint of the study was infarct size evaluated by the area under the curve of CK-MB, and the important secondary outcomes were the change in volume of infarcted myocardium on cardiac MRI, myocardial function and TIMI flow grade. The investigators concluded that MTP-131 had good safety outcomes but was not associated with any significant improvement in primary or secondary outcomes [109]. No further studies are planned for MTP-131 in ACS patients. It is now investigated for mitochondrial disorders.
Coronary no-reflow in the modern era: a review of advances in diagnostic techniques and contemporary management
Published in Expert Review of Cardiovascular Therapy, 2019
Jathinder Kumar, Cormac T O’Connor, Rajesh Kumar, Samer Khalil Arnous, Thomas J. Kiernan
In addition to established agents, several medications with novel mechanisms are under investigation for acute coronary syndrome. Whilst not in the specific context of no-reflow, their mechanism of action and improvement in outcome warrants their discussion as potential therapies for no-reflow. A number of agents have shown promise in improving outcomes in MI, and whilst not specifically studied for no-reflow, have shown reduced infarct burden of CMR. Bendavia is one such agent, and is a mitochondrially directed peptide that increases mitochondrial ATP synthesis [150]. The EMBRACE STEMI study for this agent was a Phase IIb trial involving 118 patients with a first anterior STEMI, with the drug being administered at the time of PPCI [151]. Initial findings were presented which showed no difference in the primary end-point of a significant difference in AUC of creatinine kinase-MB between bendavia and placebo groups [152]. Despite an opinion of unclear efficacy [153], ongoing research is taking place in order to clarify dose and mode/time-sequence of administration, and there have been some promising results in animal models [154].