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David J. Marcinek
Department of Radiology, University of Washington, Seattle, Washington, United States of America

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Research article
Published: 15 July 2021 in PLoS ONE
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Background Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial. Methods Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling (ATP supply per O2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions. Results A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATPmax; P = 0.055, %ΔATPmax; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI. Conclusions These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

ACS Style

Baback Roshanravan; Sophia Z. Liu; Amir S. Ali; Eric G. Shankland; Chessa Goss; John K. Amory; H. Thomas Robertson; David J. Marcinek; Kevin E. Conley. In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial. PLoS ONE 2021, 16, e0253849 .

AMA Style

Baback Roshanravan, Sophia Z. Liu, Amir S. Ali, Eric G. Shankland, Chessa Goss, John K. Amory, H. Thomas Robertson, David J. Marcinek, Kevin E. Conley. In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial. PLoS ONE. 2021; 16 (7):e0253849.

Chicago/Turabian Style

Baback Roshanravan; Sophia Z. Liu; Amir S. Ali; Eric G. Shankland; Chessa Goss; John K. Amory; H. Thomas Robertson; David J. Marcinek; Kevin E. Conley. 2021. "In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial." PLoS ONE 16, no. 7: e0253849.

Original article
Published: 10 June 2021 in Physiological Reports
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Endurance training (ET) is recommended for the elderly to improve metabolic health and aerobic capacity. However, ET-induced adaptations may be suboptimal due to oxidative stress and exaggerated inflammatory response to ET. The natural antioxidant and anti-inflammatory dietary supplement astaxanthin (AX) has been found to increase endurance performance among young athletes, but limited investigations have focused on the elderly. We tested a formulation of AX in combination with ET in healthy older adults (65–82 years) to determine if AX improves metabolic adaptations with ET, and if AX effects are sex-dependent. Forty-two subjects were randomized to either placebo (PL) or AX during 3 months of ET. Specific muscle endurance was measured in ankle dorsiflexors. Whole body exercise endurance and fat oxidation (FATox) was assessed with a graded exercise test (GXT) in conjunction with indirect calorimetry. Results: ET led to improved specific muscle endurance only in the AX group (Pre 353 ± 26 vs. Post 472 ± 41 contractions), and submaximal GXT duration improved in both groups (PL 40.8 ± 9.1% and AX 41.1 ± 6.3%). The increase in FATox at lower intensity after ET was greater in AX (PL 0.23 ± 0.15 g vs. AX 0.76 ± 0.18 g) and was associated with reduced carbohydrate oxidation and increased exercise efficiency in males but not in females.

ACS Style

Sophia Z. Liu; Ana P. Valencia; Matt P. VanDoren; Eric G. Shankland; Baback Roshanravan; Kevin E. Conley; David J. Marcinek. Astaxanthin supplementation enhances metabolic adaptation with aerobic training in the elderly. Physiological Reports 2021, 9, e14887 .

AMA Style

Sophia Z. Liu, Ana P. Valencia, Matt P. VanDoren, Eric G. Shankland, Baback Roshanravan, Kevin E. Conley, David J. Marcinek. Astaxanthin supplementation enhances metabolic adaptation with aerobic training in the elderly. Physiological Reports. 2021; 9 (11):e14887.

Chicago/Turabian Style

Sophia Z. Liu; Ana P. Valencia; Matt P. VanDoren; Eric G. Shankland; Baback Roshanravan; Kevin E. Conley; David J. Marcinek. 2021. "Astaxanthin supplementation enhances metabolic adaptation with aerobic training in the elderly." Physiological Reports 9, no. 11: e14887.

Original article
Published: 08 June 2021 in GeroScience
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Aging and poor nutrition are independent risk factors for the development of chronic disease. When young animals are given diets high in fat or sugar, they exhibit hallmarks of aging like mitochondrial dysfunction and inflammation, and also develop a greater risk for age-related disease. The same mitochondrial dysfunction and inflammation that progress with aging may also further predispose older individuals to dietary insults by fat and sugar. The purpose of this work is to review the most recent studies that address the impact of fat and sugar consumption on hallmarks of aging (mitochondrial dysfunction and inflammation). Findings from these studies show that obesogenic, high-fat diets can exacerbate age-related disease and hallmarks of aging in young animals, but high-fat diets that are non-obesogenic may play a beneficial role in old age. In contrast, high-sugar diets do not require an obesogenic effect to induce mitochondrial dysfunction or inflammation in young rodents. Currently, there is a lack of experimental studies addressing the impact of sugar in the context of aging, even though empirical evidence points to the detrimental effect of sugar in aging by contributing to a variety of age-related diseases. Mitochondrial dysfunction and altered cellular communication (e.g. inflammation) progress with advancing age and increase the risk for age-related disease (ARD). Given the physiological changes that occur with age, the impact of high-fat (HFD) and high-sugar diets (HSD) may differ in later and earlier stages of life. HFD can promote the development of hallmarks of aging in young animals and can also exacerbate the risk for ARD when consumed at an old age. However, non-obesogenic high-fat diets may also reduce the risk for ARD in old age by acting on these hallmarks of aging. On the other hand, HSD promotes mitochondrial dysfunction and inflammation without necessarily inducing weight gain in young animals. Empirical evidence points to sugar as a major contributor to age-related disease and more experimental studies are needed to clarify whether aged individuals are more susceptible to its effects

ACS Style

Ana P. Valencia; Nitin Nagaraj; Deena H. Osman; Peter S. Rabinovitch; David J. Marcinek. Are fat and sugar just as detrimental in old age? GeroScience 2021, 1 -11.

AMA Style

Ana P. Valencia, Nitin Nagaraj, Deena H. Osman, Peter S. Rabinovitch, David J. Marcinek. Are fat and sugar just as detrimental in old age? GeroScience. 2021; ():1-11.

Chicago/Turabian Style

Ana P. Valencia; Nitin Nagaraj; Deena H. Osman; Peter S. Rabinovitch; David J. Marcinek. 2021. "Are fat and sugar just as detrimental in old age?" GeroScience , no. : 1-11.

Journal article
Published: 03 June 2021 in Free Radical Biology and Medicine
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High intensity exercise is a popular mode of exercise to elicit similar or greater adaptive responses compared to traditional moderate intensity continuous exercise. However, the molecular mechanisms underlying these adaptive responses are still unclear. The purpose of this pilot study was to compare high and low intensity contractile stimulus on the Nrf2-mediated redox stress response in mouse skeletal muscle. An intra-animal design was used to control for variations in individual responses to muscle stimulation by comparing a stimulated limb (STIM) to the contralateral unstimulated control limb (CON). High Intensity (HI – 100Hz), Low Intensity (LI – 50Hz), and Naïve Control (NC – Mock stimulation vs CON) groups were used to compare these effects on Nrf2-ARE binding, Keap1 protein, and downstream gene and protein expression of Nrf2 target genes. Muscle stimulation significantly increased Nrf2-ARE binding in LI-STIM compared to LI-CON (p = 0.0098), while Nrf2-ARE binding was elevated in both HI-CON and HI-STIM compared to NC (p = 0.0007). The Nrf2-ARE results were mirrored in the downregulation of Keap1, where Keap1 expression in HI-CON and HI-STIM were both significantly lower than NC (p = 0.008) and decreased in LI-STIM compared to LI-CON (p = 0.015). In addition, stimulation increased NQO1 protein compared to contralateral control regardless of stimulation intensity (p = 0.019), and HO1 protein was significantly higher in high intensity compared to the Naïve control group (p = 0.002). Taken together, these data suggest a systemic redox signaling exerkine is activating Nrf2-ARE binding and is intensity gated, where Nrf2-ARE activation in contralateral control limbs were only seen in the HI group. Other research in exercise induced Nrf2 signaling support the general finding that Nrf2 is activated in peripheral tissues in response to exercise, however the specific exerkine responsible for the systemic signaling effects is not known. Future work should aim to delineate these redox sensitive systemic signaling mechanisms.

ACS Style

Ethan L. Ostrom; Ana P. Valencia; David J. Marcinek; Tinna Traustadóttir. High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response. Free Radical Biology and Medicine 2021, 172, 82 -89.

AMA Style

Ethan L. Ostrom, Ana P. Valencia, David J. Marcinek, Tinna Traustadóttir. High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response. Free Radical Biology and Medicine. 2021; 172 ():82-89.

Chicago/Turabian Style

Ethan L. Ostrom; Ana P. Valencia; David J. Marcinek; Tinna Traustadóttir. 2021. "High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response." Free Radical Biology and Medicine 172, no. : 82-89.

Original article
Published: 02 June 2021 in JCSM Rapid Communications
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Background Eccentric contractions induce muscle damage (EIMD) that compromises muscle function. Poor recovery from EIMD has been suggested to be a contributor to the decline in muscle function evident in sarcopenia, but it is unclear which aspects of muscle function are more susceptible to disruption by EIMD in old versus young muscle. The purpose of this study was to determine the extent of impairment in contractile function (force, fatigue, tetanus and twitch kinetics) during the recovery from EIMD in VO mice compared to young adult (YA). Methods Male CB6F1 were obtained from National Institure of Aging colony. VO mice were 29–31 months of age, and YA mice were 7–9 months of age. The plantarflexor muscles were subjected to 20 eccentric contractions in vivo to induce injury (EIMD). Changes in tetanic force and kinetics were assessed before EIMD, immediately after EIMD and 3 days after EIMD (3d-EIMD). Force–frequency and rates of fatigue were assessed 3d-EIMD and compared with baseline. Histological analysis was conducted in injured and non-injured contralateral gastrocnemius muscle. Results There was a greater loss in isometric tetanic force immediately following EIMD in VO compared with YA (−31.6% ± 10.4 vs. −21.7% ± 6.0, P < 0.05). At 3d-EIMD, the rate of contraction of tetanus began to recover in VO, but not in YA (20.8% vs. −6.8%, P < 0.05), whereas the extent of recovery of force tended to be greater in VO than YA (39.3% vs. 17.1%, P = 0.08) when compared with tetanic function immediately after injury. Compared with function pre-injury (baseline), VO and YA had similar deficits in tetanic force (−7.3% ± 5.3 vs. -9.2% ± 6.0, respectively) and kinetics at Day 3. Twitch kinetics (rate of relaxation) recovered faster in VO compared with YA. The rate of muscle fatigue was similar to baseline values, with VO continuing to be more fatigue resistant than YA 3d-EIMD. There were no detectable differences in muscle mass or myofibre cross-sectional area despite continued deficits in force following EIMD in either age group. Conclusions Despite clear functional deficits and greater susceptibility to injury, aged sarcopenic muscle exhibited a similar ability to recover contractile function to younger muscle following EIMD. In addition, neither age group showed accelerated muscle fatigue in the recovery phase after EIMD; thus, sarcopenic mouse muscles do not appear to be more susceptible to long-term functional impairment than young healthy muscles.

ACS Style

Ana P. Valencia; Ashton T. Samuelson; Rudolph Stuppard; David J. Marcinek. Functional recovery from eccentric injury is maintained in sarcopenic mouse muscle. JCSM Rapid Communications 2021, 1 .

AMA Style

Ana P. Valencia, Ashton T. Samuelson, Rudolph Stuppard, David J. Marcinek. Functional recovery from eccentric injury is maintained in sarcopenic mouse muscle. JCSM Rapid Communications. 2021; ():1.

Chicago/Turabian Style

Ana P. Valencia; Ashton T. Samuelson; Rudolph Stuppard; David J. Marcinek. 2021. "Functional recovery from eccentric injury is maintained in sarcopenic mouse muscle." JCSM Rapid Communications , no. : 1.

Preprint content
Published: 12 April 2021
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Introduction: High intensity exercise is an increasingly popular mode of exercise to elicit similar or greater adaptive responses compared to traditional moderate intensity continuous exercise. However, the molecular mechanisms underlying these adaptive responses are still unclear. The purpose of this pilot study was to compare high and low intensity contractile stimulus on the Nrf2-mediated redox stress response in mouse skeletal muscle. Methods: An intra-animal design was used to control for variations in individual responses to muscle stimulation by using a stimulated limb (STIM) and comparing to the contralateral unstimulated control limb (CON). High Intensity (HI-100Hz), Low Intensity (LI-50Hz), and Naive Control (NC-Mock stimulation vs CON) groups were used to compare these effects on Nrf2-ARE binding, Keap1 protein content, and downstream gene and protein expression of Nrf2 target genes. Results: Muscle stimulation significantly increased Nrf2-ARE binding in LI-STIM compared to LI-CON (p = 0.0098), while Nrf2-ARE binding was elevated in both HI-CON and HI-STIM compared to NC (p = 0.0007). The Nrf2-ARE results were mirrored in the down-regulation of Keap1, where Keap1 expression in HI-CON and HI-STIM were both significantly lower than NC (p = 0.008) and decreased in LI-STIM compared to LI-CON (p = 0.015). In addition, stimulation increased NQO1 protein compared to contralateral control regardless of stimulation intensity (p = 0.019). Conclusions: Taken together, these data suggest a systemic redox signaling exerkine is activating Nrf2-ARE binding and is intensity gated, where Nrf2-ARE activation in contralateral control limbs were only seen in the HI group. Other research in exercise induced Nrf2 signaling support the general finding that Nrf2 is activated in peripheral tissues in response to exercise, however the specific exerkine responsible for the systemic signaling effects is not known. Future work should aim to delineate these redox sensitive systemic signaling mechanisms.

ACS Style

Ethan Lambert Ostrom; Ana P. Valencia; David J. Marcinek; Tinna Traustadottir. High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response. 2021, 1 .

AMA Style

Ethan Lambert Ostrom, Ana P. Valencia, David J. Marcinek, Tinna Traustadottir. High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response. . 2021; ():1.

Chicago/Turabian Style

Ethan Lambert Ostrom; Ana P. Valencia; David J. Marcinek; Tinna Traustadottir. 2021. "High intensity muscle stimulation activates a systemic Nrf2-mediated redox stress response." , no. : 1.

Preprint content
Published: 06 April 2021
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Purpose Characterize how metabolic function in the murine retina and retinal pigment epithelium-choroid-sclera (eyecup) complex is impacted by natural aging. Methods We examined scotopic and photopic visual function of young (3-6 months) and aged (23-26 months) C57Bl/6J mice using electroretinograms (ERGs). Metabolic changes in retina and eyecup explants were characterized by measuring uptake and usage of U-13C-glucose or U-13C-glutamine at different timepoints by gas chromatography-mass spectrometry (GC-MS), measuring oxygen consumption rate (OCR) using a perifusion apparatus, and determining ATP levels with a bioluminescence assay. Results Scotopic and photopic ERG responses declined in aged mice. Glucose metabolism, glutamine metabolism, OCR, and ATP pools in retinal explants were mostly unaffected by the age of the mouse. In eyecups, glutamine usage in the Krebs Cycle decreased while glucose metabolism, OCR, and ATP pools remained stable. Conclusions The ex vivo approach in our study to examine aging glucose and glutamine metabolism in retina and RPE showed negligible impact of age on retina and an impairment of glutamine anaplerosis in eyecups. The surprising metabolic stability of these tissues ex vivo suggests age-related metabolic alterations in these tissues may not be intrinsic. Future experiments should focus on determining whether external factors including nutrient supply, oxygen availability, or other structural changes influence ocular metabolism in vivo.

ACS Style

Kristine A. Tsantilas; Whitney M. Cleghorn; Celia M. Bisbach; Jeremy A. Whitson; Daniel T. Hass; Brian M. Robbings; Martin Sadilek; Jonathan D. Linton; Austin M. Rountree; Ana P. Valencia; Mariya T. Sweetwyne; Matthew D. Campbell; Huiliang Zhang; Connor S.R. Jankowski; Ian R. Sweet; David J. Marcinek; Peter S. Rabinovitch; James B. Hurley. Metabolic function in aging retina and retinal pigment epithelium remains robust despite vision loss. 2021, 1 .

AMA Style

Kristine A. Tsantilas, Whitney M. Cleghorn, Celia M. Bisbach, Jeremy A. Whitson, Daniel T. Hass, Brian M. Robbings, Martin Sadilek, Jonathan D. Linton, Austin M. Rountree, Ana P. Valencia, Mariya T. Sweetwyne, Matthew D. Campbell, Huiliang Zhang, Connor S.R. Jankowski, Ian R. Sweet, David J. Marcinek, Peter S. Rabinovitch, James B. Hurley. Metabolic function in aging retina and retinal pigment epithelium remains robust despite vision loss. . 2021; ():1.

Chicago/Turabian Style

Kristine A. Tsantilas; Whitney M. Cleghorn; Celia M. Bisbach; Jeremy A. Whitson; Daniel T. Hass; Brian M. Robbings; Martin Sadilek; Jonathan D. Linton; Austin M. Rountree; Ana P. Valencia; Mariya T. Sweetwyne; Matthew D. Campbell; Huiliang Zhang; Connor S.R. Jankowski; Ian R. Sweet; David J. Marcinek; Peter S. Rabinovitch; James B. Hurley. 2021. "Metabolic function in aging retina and retinal pigment epithelium remains robust despite vision loss." , no. : 1.

Preprint content
Published: 02 October 2020
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Background: Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial. Methods: Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling (ATP supply per O2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions. Results: A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (∆ATPmax; P=0.055, %∆ATPmax; P=0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI. Conclusions: These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.

ACS Style

Baback Roshanravan; Sophia Z. Liu; Eric G. Shankland; John K. Amory; H. Thomas Robertson; David J Marcinek; Kevin E. Conley. In Vivo Mitochondrial ATP Production Is Improved in Older Adult Skeletal Muscle After a Single Dose of Elamipretide in a Randomized Trial. 2020, 1 .

AMA Style

Baback Roshanravan, Sophia Z. Liu, Eric G. Shankland, John K. Amory, H. Thomas Robertson, David J Marcinek, Kevin E. Conley. In Vivo Mitochondrial ATP Production Is Improved in Older Adult Skeletal Muscle After a Single Dose of Elamipretide in a Randomized Trial. . 2020; ():1.

Chicago/Turabian Style

Baback Roshanravan; Sophia Z. Liu; Eric G. Shankland; John K. Amory; H. Thomas Robertson; David J Marcinek; Kevin E. Conley. 2020. "In Vivo Mitochondrial ATP Production Is Improved in Older Adult Skeletal Muscle After a Single Dose of Elamipretide in a Randomized Trial." , no. : 1.

Preprint content
Published: 03 January 2020
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Aging-associated diseases, including cardiac dysfunction, are increasingly common in the population. However, the mechanisms of physiologic aging in general, and cardiac aging in particular, remain poorly understood. While effective medical interventions are available for some kinds of heart failure, one age-related impairment, diastolic dysfunction in Heart Failure with Preserved Ejection Fraction (HFpEF) is lacking a clinically effective treatment. Using the model of naturally aging mice and rats, we show direct evidence of increased proton leak in the aged heart mitochondria. Moreover, we identified ANT1 as mediating the increased proton permeability of old cardiomyocytes. Most importantly, the tetra-peptide drug SS-31 (elamipretide) prevents age-related excess proton entry, decreases the mitochondrial flash activity and mitochondrial permeability transition pore (mPTP) opening and rejuvenates mitochondrial function by direct association with ANT1 and the mitochondrial ATP synthasome. Our results uncover a novel mechanism of age-related cardiac dysfunction and elucidate how SS-31 is able to reverse this clinically important complication of cardiac aging.

ACS Style

Huiliang Zhang; Nathan N. Alder; Wang Wang; Hazel Szeto; David J. Marcinek; Peter S. Rabinovitch. Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte. 2020, 1 .

AMA Style

Huiliang Zhang, Nathan N. Alder, Wang Wang, Hazel Szeto, David J. Marcinek, Peter S. Rabinovitch. Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte. . 2020; ():1.

Chicago/Turabian Style

Huiliang Zhang; Nathan N. Alder; Wang Wang; Hazel Szeto; David J. Marcinek; Peter S. Rabinovitch. 2020. "Reduction of Elevated Proton Leak Rejuvenates Mitochondria in the Aged Cardiomyocyte." , no. : 1.

Preprint content
Published: 02 January 2020
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Diastolic dysfunction is a prominent feature of cardiac aging in both mice and humans. We show here that 8-week treatment of old mice with the mitochondrial targeted peptide SS-31 (elamipretide) can substantially reverse this deficit. SS-31 normalized the increase in proton leak and reduced mitochondrial ROS in cardiomyocytes from old mice, accompanied by reduced protein oxidation and a shift towards a more reduced protein thiol redox state in old hearts. Improved diastolic function was concordant with increased phosphorylation of cMyBP-C Ser282 but was independent of titin isoform shift. Late-life viral expression of mitochondrial-targeted catalase (mCAT) produced similar functional benefits in old mice and SS-31 did not improve cardiac function of old mCAT mice, implicating normalizing mitochondrial oxidative stress as an overlapping mechanism. 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 for cardiac aging.

ACS Style

Ying Ann Chiao; Huiliang Zhang; Mariya Sweetwyne; Jeremy Whitson; Ying Sonia Ting; Nathan Basisty; Lindsay Pino; Ellen Quarles; Ngoc-Han Nguyen; Matthew D. Campbell; Tong Zhang; Matthew J. Gaffrey; Gennifer Merrihew; Lu Wang; Yongping Yue; Dongsheng Duan; Henk Granzier; Hazel H. Szeto; Wei-Jun Qian; David Marcinek; Michael J. MacCoss; Peter S. Rabinovitch. Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. 2020, 1 .

AMA Style

Ying Ann Chiao, Huiliang Zhang, Mariya Sweetwyne, Jeremy Whitson, Ying Sonia Ting, Nathan Basisty, Lindsay Pino, Ellen Quarles, Ngoc-Han Nguyen, Matthew D. Campbell, Tong Zhang, Matthew J. Gaffrey, Gennifer Merrihew, Lu Wang, Yongping Yue, Dongsheng Duan, Henk Granzier, Hazel H. Szeto, Wei-Jun Qian, David Marcinek, Michael J. MacCoss, Peter S. Rabinovitch. Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice. . 2020; ():1.

Chicago/Turabian Style

Ying Ann Chiao; Huiliang Zhang; Mariya Sweetwyne; Jeremy Whitson; Ying Sonia Ting; Nathan Basisty; Lindsay Pino; Ellen Quarles; Ngoc-Han Nguyen; Matthew D. Campbell; Tong Zhang; Matthew J. Gaffrey; Gennifer Merrihew; Lu Wang; Yongping Yue; Dongsheng Duan; Henk Granzier; Hazel H. Szeto; Wei-Jun Qian; David Marcinek; Michael J. MacCoss; Peter S. Rabinovitch. 2020. "Late-life restoration of mitochondrial function reverses cardiac dysfunction in old mice." , no. : 1.

Preprint content
Published: 18 August 2019
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Mitochondrial dysfunction underlies the etiology of a broad spectrum of diseases including heart disease, cancer, neurodegenerative diseases, and the general aging process. Therapeutics that restore healthy mitochondrial function hold promise for treatment of these conditions. The synthetic tetrapeptide, elamipretide (SS-31), improves mitochondrial function, but mechanistic details of its pharmacological effects are unknown. Reportedly, SS-31 primarily interacts with the phospholipid cardiolipin in the inner mitochondrial membrane. Here we utilize chemical cross-linking with mass spectrometry to identify protein interactors of SS-31 in mitochondria. The SS-31-interacting proteins, all known cardiolipin binders, fall into two groups, those involved in ATP production through the oxidative phosphorylation pathway and those involved in 2-oxoglutarate metabolic processes. Residues cross-linked with SS-31 reveal binding regions that in many cases, are proximal to cardiolipin-protein interacting regions. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy.Significance StatementSS-31 is a synthetic peptide that improves mitochondrial function and is currently undergoing clinical trials for treatments of heart failure, primary mitochondrial myopathy, and other mitochondrial diseases. SS-31 interacts with cardiolipin which is abundant in the inner mitochondrial membrane, but mechanistic details of its pharmacological effects are unknown. Here we apply a novel chemical cross-linking/mass spectrometry method to provide the first direct evidence for specific interactions between SS-31 and mitochondrial proteins. The identified SS-31 interactors are functional components in ATP production and 2-oxoglutarate metabolism and signaling, consistent with improved mitochondrial function resultant from SS-31 treatment. These results offer the first glimpse of the protein interaction landscape of SS-31 and provide new mechanistic insight relevant to SS-31 mitochondrial therapy.

ACS Style

Juan D. Chavez; Xiaoting Tang; Matthew D. Campbell; Gustavo Reyes; Philip A. Kramer; Rudy Stuppard; Andrew Keller; David J. Marcinek; James E. Bruce. Mitochondrial protein interaction landscape of SS-31. 2019, 739128 .

AMA Style

Juan D. Chavez, Xiaoting Tang, Matthew D. Campbell, Gustavo Reyes, Philip A. Kramer, Rudy Stuppard, Andrew Keller, David J. Marcinek, James E. Bruce. Mitochondrial protein interaction landscape of SS-31. . 2019; ():739128.

Chicago/Turabian Style

Juan D. Chavez; Xiaoting Tang; Matthew D. Campbell; Gustavo Reyes; Philip A. Kramer; Rudy Stuppard; Andrew Keller; David J. Marcinek; James E. Bruce. 2019. "Mitochondrial protein interaction landscape of SS-31." , no. : 739128.

Journal article
Published: 23 May 2019 in Toxins
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Domoic acid (DA)-producing harmful algal blooms (HABs) have been present at unprecedented geographic extent and duration in recent years causing an increase in contamination of seafood by this common environmental neurotoxin. The toxin is responsible for the neurotoxic illness, amnesic shellfish poisoning (ASP), that is characterized by gastro-intestinal distress, seizures, memory loss, and death. Established seafood safety regulatory limits of 20 μg DA/g shellfish have been relatively successful at protecting human seafood consumers from short-term high-level exposures and episodes of acute ASP. Significant concerns, however, remain regarding the potential impact of repetitive low-level or chronic DA exposure for which there are no protections. Here, we report the novel discovery of a DA-specific antibody in the serum of chronically-exposed tribal shellfish harvesters from a region where DA is commonly detected at low levels in razor clams year-round. The toxin was also detected in tribal shellfish consumers' urine samples confirming systemic DA exposure via consumption of legally-harvested razor clams. The presence of a DA-specific antibody in the serum of human shellfish consumers confirms long-term chronic DA exposure and may be useful as a diagnostic biomarker in a clinical setting. Adverse effects of chronic low-level DA exposure have been previously documented in laboratory animal studies and tribal razor clam consumers, underscoring the potential clinical impact of such a diagnostic biomarker for protecting human health. The discovery of this type of antibody response to chronic DA exposure has broader implications for other environmental neurotoxins of concern.

ACS Style

Kathi A. Lefebvre; Betsy Jean Yakes; Elizabeth Frame; Preston Kendrick; Sara Shum; Nina Isoherranen; Bridget E. Ferriss; Alison Robertson; Alicia Hendrix; David J. Marcinek; Lynn Grattan. Discovery of a Potential Human Serum Biomarker for Chronic Seafood Toxin Exposure Using an SPR Biosensor. Toxins 2019, 11, 293 .

AMA Style

Kathi A. Lefebvre, Betsy Jean Yakes, Elizabeth Frame, Preston Kendrick, Sara Shum, Nina Isoherranen, Bridget E. Ferriss, Alison Robertson, Alicia Hendrix, David J. Marcinek, Lynn Grattan. Discovery of a Potential Human Serum Biomarker for Chronic Seafood Toxin Exposure Using an SPR Biosensor. Toxins. 2019; 11 (5):293.

Chicago/Turabian Style

Kathi A. Lefebvre; Betsy Jean Yakes; Elizabeth Frame; Preston Kendrick; Sara Shum; Nina Isoherranen; Bridget E. Ferriss; Alison Robertson; Alicia Hendrix; David J. Marcinek; Lynn Grattan. 2019. "Discovery of a Potential Human Serum Biomarker for Chronic Seafood Toxin Exposure Using an SPR Biosensor." Toxins 11, no. 5: 293.

Journal article
Published: 28 December 2018 in Free Radical Biology and Medicine
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Sarcopenia and exercise intolerance are major contributors to reduced quality of life in the elderly for which there are few effective treatments. We tested whether enhancing mitochondrial function and reducing mitochondrial oxidant production with SS-31 (elamipretide) could restore redox balance and improve skeletal muscle function in aged mice. Young (5 mo) and aged (26 mo) female C57BL/6Nia mice were treated for 8-weeks with 3 mg/kg/day SS-31. Mitochondrial function was assessed in vivo using 31P and optical spectroscopy. SS-31 reversed age-related decline in maximum mitochondrial ATP production (ATPmax) and coupling of oxidative phosphorylation (P/O). Despite the increased in vivo mitochondrial capacity, mitochondrial protein expression was either unchanged or reduced in the treated aged mice and respiration in permeabilized gastrocnemius (GAS) fibers was not different between the aged and aged+SS-31 mice. Treatment with SS-31 also restored redox homeostasis in the aged skeletal muscle. The glutathione redox status was more reduced and thiol redox proteomics indicated a robust reversal of cysteine S-glutathionylation post-translational modifications across the skeletal muscle proteome. The gastrocnemius in the age+SS-31 mice was more fatigue resistant with significantly greater mass compared to aged controls. This contributed to a significant increase in treadmill endurance compared to both pretreatment and untreated control values. These results demonstrate that the shift of redox homeostasis due to mitochondrial oxidant production in aged muscle is a key factor in energetic defects and exercise intolerance. Treatment with SS-31 restores redox homeostasis, improves mitochondrial quality, and increases exercise tolerance without an increase in mitochondrial content. Since elamipretide is currently in clinical trials these results indicate it may have direct translational value for improving exercise tolerance and quality of life in the elderly.

ACS Style

Matthew D. Campbell; Jicheng Duan; Ashton T. Samuelson; Matthew J. Gaffrey; Gennifer E. Merrihew; Jarrett D. Egertson; Lu Wang; Theo K. Bammler; Ronald J. Moore; Collin C. White; Terrance J. Kavanagh; Joachim G. Voss; Hazel H. Szeto; Peter S. Rabinovitch; Michael J. MacCoss; Wei-Jun Qian; David J. Marcinek. Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice. Free Radical Biology and Medicine 2018, 134, 268 -281.

AMA Style

Matthew D. Campbell, Jicheng Duan, Ashton T. Samuelson, Matthew J. Gaffrey, Gennifer E. Merrihew, Jarrett D. Egertson, Lu Wang, Theo K. Bammler, Ronald J. Moore, Collin C. White, Terrance J. Kavanagh, Joachim G. Voss, Hazel H. Szeto, Peter S. Rabinovitch, Michael J. MacCoss, Wei-Jun Qian, David J. Marcinek. Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice. Free Radical Biology and Medicine. 2018; 134 ():268-281.

Chicago/Turabian Style

Matthew D. Campbell; Jicheng Duan; Ashton T. Samuelson; Matthew J. Gaffrey; Gennifer E. Merrihew; Jarrett D. Egertson; Lu Wang; Theo K. Bammler; Ronald J. Moore; Collin C. White; Terrance J. Kavanagh; Joachim G. Voss; Hazel H. Szeto; Peter S. Rabinovitch; Michael J. MacCoss; Wei-Jun Qian; David J. Marcinek. 2018. "Improving mitochondrial function with SS-31 reverses age-related redox stress and improves exercise tolerance in aged mice." Free Radical Biology and Medicine 134, no. : 268-281.

Journal article
Published: 23 May 2018 in Redox Biology
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Protein S-glutathionylation is an important reversible post-translational modification implicated in redox signaling. Oxidative modifications to protein thiols can alter the activity of metabolic enzymes, transcription factors, kinases, phosphatases, and the function of contractile proteins. However, the extent to which muscle contraction induces oxidative modifications in redox sensitive thiols is not known. The purpose of this study was to determine the targets of S-glutathionylation redox signaling following fatiguing contractions. Anesthetized adult male CB6F1 (BALB/cBy × C57BL/6) mice were subjected to acute fatiguing contractions for 15 min using in vivo stimulations. The right (stimulated) and left (unstimulated) gastrocnemius muscleswere collected 60 min after the last stimulation and processed for redox proteomics assay of S-glutathionylation. Using selective reduction with a glutaredoxin enzyme cocktail and resin-assisted enrichment technique, we quantified the levels of site-specific protein S-glutathionylation at rest and following fatiguing contractions. Redox proteomics revealed over 2200 sites of S-glutathionylation modifications, of which 1290 were significantly increased after fatiguing contractions. Muscle contraction leads to the greatest increase in S-glutathionylation in the mitochondria (1.03%) and the smallest increase in the nucleus (0.47%). Regulatory cysteines were significantly S-glutathionylated on mitochondrial complex I and II, GAPDH, MDH1, ACO2, and mitochondrial complex V among others. Similarly, S-glutathionylation of RYR1, SERCA1, titin, and troponin I2 are known to regulate muscle contractility and were significantly S-glutathionylated after just 15 min of fatiguing contractions. The largest fold changes (> 1.6) in the S-glutathionylated proteome after fatigue occurred on signaling proteins such as 14-3-3 protein gamma and MAP2K4, as well as proteins like SERCA1, and NDUV2 of mitochondrial complex I, at previously unknown glutathionylation sites. These findings highlight the important role of redox control over muscle physiology, metabolism, and the exercise adaptive response. This study lays the groundwork for future investigation into the altered exercise adaptation associated with chronic conditions, such as sarcopenia.

ACS Style

Philip Kramer; Jicheng Duan; Matthew J. Gaffrey; Anil K. Shukla; Lu Wang; Theo K. Bammler; Wei-Jun Qian; David J. Marcinek. Fatiguing contractions increase protein S-glutathionylation occupancy in mouse skeletal muscle. Redox Biology 2018, 17, 367 -376.

AMA Style

Philip Kramer, Jicheng Duan, Matthew J. Gaffrey, Anil K. Shukla, Lu Wang, Theo K. Bammler, Wei-Jun Qian, David J. Marcinek. Fatiguing contractions increase protein S-glutathionylation occupancy in mouse skeletal muscle. Redox Biology. 2018; 17 ():367-376.

Chicago/Turabian Style

Philip Kramer; Jicheng Duan; Matthew J. Gaffrey; Anil K. Shukla; Lu Wang; Theo K. Bammler; Wei-Jun Qian; David J. Marcinek. 2018. "Fatiguing contractions increase protein S-glutathionylation occupancy in mouse skeletal muscle." Redox Biology 17, no. : 367-376.

Journal article
Published: 01 November 2017 in Free Radical Biology and Medicine
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Philip Kramer; Jicheng Duan; Matthew J. Gaffrey; Lu Wang; Theo K. Bammler; Wei-Jun Qian; David J. Marcinek. Fatiguing Contractions Induce Acute Redox Signaling in Mouse Muscle. Free Radical Biology and Medicine 2017, 112, 191 -192.

AMA Style

Philip Kramer, Jicheng Duan, Matthew J. Gaffrey, Lu Wang, Theo K. Bammler, Wei-Jun Qian, David J. Marcinek. Fatiguing Contractions Induce Acute Redox Signaling in Mouse Muscle. Free Radical Biology and Medicine. 2017; 112 ():191-192.

Chicago/Turabian Style

Philip Kramer; Jicheng Duan; Matthew J. Gaffrey; Lu Wang; Theo K. Bammler; Wei-Jun Qian; David J. Marcinek. 2017. "Fatiguing Contractions Induce Acute Redox Signaling in Mouse Muscle." Free Radical Biology and Medicine 112, no. : 191-192.

Journal article
Published: 18 January 2017 in Environment International
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Domoic acid (DA) is a neurotoxin that is naturally produced by phytoplankton and accumulates in seafood during harmful algal blooms. As the prevalence of DA increases in the marine environment, there is a critical need to identify seafood consumers at risk of DA poisoning. DA exposure was estimated in recreational razor clam (Siliqua patula) harvesters to determine if exposures above current regulatory guidelines occur and/or if harvesters are chronically exposed to low levels of DA. Human consumption rates of razor clams were determined by distributing 1523 surveys to recreational razor clam harvesters in spring 2015 and winter 2016, in Washington, USA. These consumption rate data were combined with DA measurements in razor clams, collected by a state monitoring program, to estimate human DA exposure. Approximately 7% of total acute exposures calculated (including the same individuals at different times) exceeded the current regulatory reference dose (0.075 mg DA·kg bodyweight− 1·d− 1) due to higher than previously reported consumption rates, lower bodyweights, and/or by consumption of clams at the upper range of legal DA levels (maximum 20 mg·kg− 1 wet weight for whole tissue). Three percent of survey respondents were potentially at risk of chronic DA exposure by consuming a minimum of 15 clams per month for at 12 consecutive months. These insights into DA consumption will provide an additional tool for razor clam fishery management.

ACS Style

Bridget E. Ferriss; David J. Marcinek; Daniel Ayres; Jerry Borchert; Kathi A. Lefebvre. Acute and chronic dietary exposure to domoic acid in recreational harvesters: A survey of shellfish consumption behavior. Environment International 2017, 101, 70 -79.

AMA Style

Bridget E. Ferriss, David J. Marcinek, Daniel Ayres, Jerry Borchert, Kathi A. Lefebvre. Acute and chronic dietary exposure to domoic acid in recreational harvesters: A survey of shellfish consumption behavior. Environment International. 2017; 101 ():70-79.

Chicago/Turabian Style

Bridget E. Ferriss; David J. Marcinek; Daniel Ayres; Jerry Borchert; Kathi A. Lefebvre. 2017. "Acute and chronic dietary exposure to domoic acid in recreational harvesters: A survey of shellfish consumption behavior." Environment International 101, no. : 70-79.

Review
Published: 05 November 2016 in Heart Failure Reviews
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Changes in mitochondrial capacity and quality play a critical role in skeletal and cardiac muscle dysfunction. In vivo measurements of mitochondrial capacity provide a clear link between physical activity and mitochondrial function in aging and heart failure, although the cause and effect relationship remains unclear. Age-related decline in mitochondrial quality leads to mitochondrial defects that affect redox, calcium, and energy-sensitive signaling by altering the cellular environment that can result in skeletal muscle dysfunction independent of reduced mitochondrial capacity. This reduced mitochondrial quality with age is also likely to sensitize skeletal muscle mitochondria to elevated angiotensin or beta-adrenergic signaling associated with heart failure. This synergy between aging and heart failure could further disrupt cell energy and redox homeostasis and contribute to exercise intolerance in this patient population. Therefore, the interaction between aging and heart failure, particularly with respect to mitochondrial dysfunction, should be a consideration when developing strategies to improve quality of life in heart failure patients. Given the central role of the mitochondria in skeletal and cardiac muscle dysfunction, mitochondrial quality may provide a common link for targeted interventions in these populations.

ACS Style

Sophia Z. Liu; David J. Marcinek. Skeletal muscle bioenergetics in aging and heart failure. Heart Failure Reviews 2016, 22, 167 -178.

AMA Style

Sophia Z. Liu, David J. Marcinek. Skeletal muscle bioenergetics in aging and heart failure. Heart Failure Reviews. 2016; 22 (2):167-178.

Chicago/Turabian Style

Sophia Z. Liu; David J. Marcinek. 2016. "Skeletal muscle bioenergetics in aging and heart failure." Heart Failure Reviews 22, no. 2: 167-178.

Journal article
Published: 01 November 2016 in Free Radical Biology and Medicine
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Matthew D. Campbell; Gary Knowles; Kevin Kilroy; Ashton T. Samuleson; Matthew J. Gaffrey; Collin C. White; Terrance J. Kavanagh; Wei-Jun Qian; David J. Marcinek. Improved Redox State Increases Aged Skeletal Muscle Performance. Free Radical Biology and Medicine 2016, 100, S81 .

AMA Style

Matthew D. Campbell, Gary Knowles, Kevin Kilroy, Ashton T. Samuleson, Matthew J. Gaffrey, Collin C. White, Terrance J. Kavanagh, Wei-Jun Qian, David J. Marcinek. Improved Redox State Increases Aged Skeletal Muscle Performance. Free Radical Biology and Medicine. 2016; 100 ():S81.

Chicago/Turabian Style

Matthew D. Campbell; Gary Knowles; Kevin Kilroy; Ashton T. Samuleson; Matthew J. Gaffrey; Collin C. White; Terrance J. Kavanagh; Wei-Jun Qian; David J. Marcinek. 2016. "Improved Redox State Increases Aged Skeletal Muscle Performance." Free Radical Biology and Medicine 100, no. : S81.

Review article
Published: 17 December 2015 in Biochimica et Biophysica Acta (BBA) - Bioenergetics
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It is now clear that mitochondria are involved as either a cause or consequence of many chronic diseases. This central role of the mitochondria is due to their position in the cell as important integrators of cellular energetics and signaling. Mitochondrial function affects many aspects of the cellular environment such as redox homeostasis and calcium signaling, which then also exert control over mitochondrial function. This complex dynamic between mitochondrial function and the cellular environment highlights the value of examining mitochondria in vivo in the intact physiological environment. This review discusses NMR and optical approaches used to measure mitochondria ATP and oxygen fluxes that provide in vivo measures of mitochondrial capacity and quality in animal and human models. Combining these in vivo measurements with more traditional ex vivo analyses can lead to new insights into the importance of the cellular environment in controlling mitochondrial function under pathological conditions. Interpretation and underlying assumptions for each technique are discussed with the goal of providing an overview of some of the most common approaches used to measure in vivo mitochondrial function encountered in the literature.

ACS Style

Matthew D. Campbell; David J. Marcinek. Evaluation of in vivo mitochondrial bioenergetics in skeletal muscle using NMR and optical methods. Biochimica et Biophysica Acta (BBA) - Bioenergetics 2015, 1862, 716 -724.

AMA Style

Matthew D. Campbell, David J. Marcinek. Evaluation of in vivo mitochondrial bioenergetics in skeletal muscle using NMR and optical methods. Biochimica et Biophysica Acta (BBA) - Bioenergetics. 2015; 1862 (4):716-724.

Chicago/Turabian Style

Matthew D. Campbell; David J. Marcinek. 2015. "Evaluation of in vivo mitochondrial bioenergetics in skeletal muscle using NMR and optical methods." Biochimica et Biophysica Acta (BBA) - Bioenergetics 1862, no. 4: 716-724.

Review article
Published: 25 November 2015 in Frontiers in Physiology
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Mitochondrial oxidative stress is a common feature of skeletal myopathies across multiple conditions; however, the mechanism by which it contributes to skeletal muscle dysfunction remains controversial. Oxidative damage to proteins, lipids, and DNA has received the most attention, yet an important role for reversible redox post-translational modifications (PTMs) in pathophysiology is emerging. The possibility that these PTMs can exert dynamic control of muscle function implicates them as a mechanism contributing to skeletal muscle dysfunction in chronic disease. Herein, we discuss the significance of thiol-based redox dependent modifications to mitochondrial, myofibrillar and excitation-contraction (EC) coupling proteins with an emphasis on how these changes could alter skeletal muscle performance under chronically stressed conditions. A major barrier to a better mechanistic understanding of the role of reversible redox PTMs in muscle function is the technical challenges associated with accurately measuring the changes of site-specific redox PTMs. Here we will critically review current approaches with an emphasis on sample preparation artifacts, quantitation, and specificity. Despite these challenges, the ability to accurately quantify reversible redox PTMs is critical to understanding the mechanisms by which mitochondrial oxidative stress contributes to skeletal muscle dysfunction in chronic diseases.

ACS Style

Philip Kramer; Jicheng Duan; Wei-Jun Qian; David J. Marcinek. The Measurement of Reversible Redox Dependent Post-translational Modifications and Their Regulation of Mitochondrial and Skeletal Muscle Function. Frontiers in Physiology 2015, 6, 1 .

AMA Style

Philip Kramer, Jicheng Duan, Wei-Jun Qian, David J. Marcinek. The Measurement of Reversible Redox Dependent Post-translational Modifications and Their Regulation of Mitochondrial and Skeletal Muscle Function. Frontiers in Physiology. 2015; 6 ():1.

Chicago/Turabian Style

Philip Kramer; Jicheng Duan; Wei-Jun Qian; David J. Marcinek. 2015. "The Measurement of Reversible Redox Dependent Post-translational Modifications and Their Regulation of Mitochondrial and Skeletal Muscle Function." Frontiers in Physiology 6, no. : 1.