Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice

Campbell, Matthew D.; Duan, Jicheng; Samuelson, Ashton T.; Gaffrey, Matthew J.; Merrihew, Gennifer E.; Egertson, Jarrett D.; Wang, Lu; Bammler, Theo K.; Moore, Ronald J.; White, Collin C.; Kavanagh, Terrance J.; Voss, Joachim; Szeto, Hazel H.; Rabinovitch, Peter S.; MacCoss, Michael J.; Qian, Weijun; Marcinek, David J.

doi:10.1016/j.freeradbiomed.2018.12.031

Cited by 113 publications

(143 citation statements)

References 70 publications

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“…We observed reduced treadmill running time in old mice compared to young mice, and our old mice treated with SS-31 for 8 weeks ran significantly longer than old control mice ( Fig. 1f), consistent with recent observations 16 .…”

Section: -Weeks Ss-31 Treatment Rescues Cardiac Dysfunction and Hypesupporting

confidence: 92%

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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Section: -Weeks Ss-31 Treatment Rescues Cardiac Dysfunction and Hypesupporting

confidence: 92%

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

Chiao

Zhang

Sweetwyne

et al. 2020

Preprint

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“…Another cohort of mice was treated with SS-31 or vehicle control. Mice were treated daily with ip injections of 3 mg/kg SS-31 or vehicle (saline) control based on previous publications demonstrating efficacy of this dose in mouse skeletal muscle 38,48 . Sciatic nerve transection and sham surgeries were performed on the fourth day of SS-31 or vehicle injection treatment and mice were euthanized seven days later.…”

Section: Methodsmentioning

confidence: 99%

Targeting cPLA2 derived lipid hydroperoxides as a potential intervention for sarcopenia

Pharaoh

Brown

Sataranatarajan

et al. 2020

Sci Rep

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Defects in neuromuscular innervation contribute significantly to the age-related decline in muscle mass and function (sarcopenia). Our previous studies demonstrated that denervation induces muscle mitochondrial hydroperoxide production (H 2 o 2 and lipid hydroperoxides (LOOHs)). Here we define the relative contribution of mitochondrial electron transport chain (ETC) derived H 2 o 2 versus cytosolic phospholipase A 2 (cPLA 2) derived LOOHs in neurogenic muscle atrophy. We show that denervation increases muscle cPLA 2 protein content, activity, and metabolites downstream of cPLA 2 including LOOHs. Increased scavenging of mitochondrial H 2 o 2 does not protect against denervation atrophy, suggesting ETC generated H 2 o 2 is not a critical player. In contrast, inhibition of cPLA 2 in vivo mitigates LOOH production and muscle atrophy and maintains individual muscle fiber size while decreasing oxidative damage. Overall, we show that loss of innervation in several muscle atrophy models including aging induces generation of LOOHs produced by arachidonic acid metabolism in the cPLA 2 pathway contributing to loss of muscle mass. The pathological age-related loss of skeletal muscle mass and function (sarcopenia) contributes to decreased quality of life and independence and increases the risk of injury and chronic disease 1,2. Preventing or reducing the effects of sarcopenia could increase quality of life, reduce risk of comorbidity development, and save billions of dollars in healthcare costs annually. Designing therapeutic interventions will remain difficult until the complex pathways and processes underlying sarcopenia are identified 3. Studies supporting a loss of innervation with age and a link between denervation and decreased muscle fiber size suggest that sarcopenia is a form of neurogenic atrophy 4-6. In addition to the loss of muscle mass, contractile force also declines with age 7. Loss of muscle strength occurs more rapidly than can be explained by the loss of muscle mass alone, and evidence suggests that a reduction in muscle quality and neuromuscular junction signaling also play a role in the functional decline of aging muscle 8. Our previous studies using mice lacking the cytosolic superoxide (O 2 −) scavenger CuZn superoxide dismutase (CuZn SOD, Sod1 −/−) demonstrate that elevated oxidative stress leads to an accelerated sarcopenia in the Sod1 −/− mice that is characterized by denervation, muscle hydroperoxide production, and muscle atrophy 9-11. Returning expression of CuZnSOD specifically to motor neurons of the Sod1 −/− mice prevented denervation, muscle hydroperoxide production, and atrophy, supporting a link between loss of innervation, hydroperoxides, and muscle atrophy 12. We have also shown that loss of innervation to skeletal muscle directly induces basal hydroperoxide production from isolated mitochondria including both hydrogen peroxide (H 2 O 2) and lipid hydroperoxides (LOOHs) 11. The magnitude of this

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“…Elamipretide (SS-31) is a mitochondrial-targeted tetrapeptide that interacts with cardiolipin. It has been proposed that elamipretide stabilizes cardiolipin, thereby reducing ROS production and preserving ETS function under stressed conditions, [313][314][315] and might improve supercomplex stability. Elamipretide improved calcium retention capacity in cardiac mitochondria, and reduced infarct size in the hearts of STZtreated rats.…”

Section: Improving Mitochondrial Functionmentioning

confidence: 99%

Altered mitochondrial metabolism in the insulin‐resistant heart

et al. 2019

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Obesity‐induced insulin resistance and type 2 diabetes mellitus can ultimately result in various complications, including diabetic cardiomyopathy. In this case, cardiac dysfunction is characterized by metabolic disturbances such as impaired glucose oxidation and an increased reliance on fatty acid (FA) oxidation. Mitochondrial dysfunction has often been associated with the altered metabolic function in the diabetic heart, and may result from FA‐induced lipotoxicity and uncoupling of oxidative phosphorylation. In this review, we address the metabolic changes in the diabetic heart, focusing on the loss of metabolic flexibility and cardiac mitochondrial function. We consider the alterations observed in mitochondrial substrate utilization, bioenergetics and dynamics, and highlight new areas of research which may improve our understanding of the cause and effect of cardiac mitochondrial dysfunction in diabetes. Finally, we explore how lifestyle (nutrition and exercise) and pharmacological interventions can prevent and treat metabolic and mitochondrial dysfunction in diabetes.

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Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice

Cited by 113 publications

References 70 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

Targeting cPLA2 derived lipid hydroperoxides as a potential intervention for sarcopenia

Altered mitochondrial metabolism in the insulin‐resistant heart

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