In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial

Roshanravan, Baback; Liu, Sophia Z.; Ali, Amir S.; Shankland, Eric G.; Goss, Chessa; Amory, John K.; Robertson, H. Thomas; Marcinek, David J.; Conley, Kevin E.

doi:10.1371/journal.pone.0253849

Cited by 28 publications

(22 citation statements)

References 46 publications

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“…Elam also had a positive effect on physical performance, increasing age-related muscle strength and agility, as shown by grip strength and rotarod data. This is supported by several studies as Elam is known to counter age-related muscle fatigue and reverse the mitochondrial deficits of ATP production in skeletal muscle [3]. Interestingly, our data only supports this for male mice, with no difference in physical performance between Elam and control-treated female mice; even though Elam has been shown in past studies to improve exercise tolerance in females as well as males [9,21].…”

Section: Discussionsupporting

confidence: 84%

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Long-term treatment with Elamipretide enhances healthy aging phenotypes in mice

Nickel¹,

Zhu²,

Mangalindan³

et al. 2022

APT

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Disruption of metabolic and bioenergetic homeostasis related to mitochondrial dysfunction is a key driver of aging biology. Therefore, targeting mitochondrial function would be a rational approach to slowing aging. Elamipretide (Elam, a.k.a. SS-31) is a peptide known to target mitochondria and suppress mammalian signs of aging. The present study was designed to examine the phenotypic effects of long-term Elam treatment on aging in C57BL/6 mice starting at 18 months of age. Mice were fed regular chow (RC diet) or a diet high in fat and sugar (HF diet) and treated with 3 mg/kg of Elam or saline subcutaneously 5 days per week for 10 months. Physiological performance assessments were conducted at 28 months of age. Elam improved the physical performance of males but not females, while in females Elam improved cognitive performance and enhanced the maintenance of body weight and fat mass. It also improved diastolic function in both males and females, but to a greater extent in males. The HF diet over 10 months had a negative effect on health span, as it increased body fat and decreased muscle strength and heart function, especially in females. In conclusion, Elam enhanced healthy aging and cardiac function in both male and female mice, although the specific effects on function differed between sexes. In females, the treatment led to better cognitive performance and maintenance of body composition, while in males, performance on a rotating rod was preserved. These overall observations have translational implications for considering additional studies using Elam in therapeutic or preventive approaches for aging and age-related diseases. Keywords: Aging, mitochondria, elamipretide, C57BL/6 mice, high fat and sugar diet

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Section: Discussionsupporting

confidence: 84%

“…Enhancing mitochondrial function can delay or reverse some of the untoward effects of aging by targeting metabolic and bioenergetic processes [1,2,3]. Several reports have focused on mitochondrial-targeted catalase, a reac-tive oxygen species (ROS) scavenger that was found to be protective of a number of aging phenotypes [4,5,6,7].…”

Section: Introductionmentioning

confidence: 99%

Long-term treatment with Elamipretide enhances healthy aging phenotypes in mice

Nickel¹,

Zhu²,

Mangalindan³

et al. 2022

APT

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“…To test whether PD was associated with mitochondrial dysfunction in the skeletal muscle the ATPmax was assessed in the FDI and TA muscles in the PD subjects and compared with data from healthy age-matched controls from previously published clinical trials [ 31 , 32 , 33 ]. In the TA, the ATPmax was significantly reduced in the PD subjects relative to the control group ( Figure 2 A, Table 2 ), while there was no difference in ATPmax in the FDI between the PD and control subject groups ( Figure 2 B, Table 2 ).…”

Section: Resultsmentioning

confidence: 99%

“…All study procedures took place at the Translational Bioenergetics Laboratory (TBL) human research lab in the UW Department of Radiology in Seattle, WA, USA. Control data from healthy age-matched subjects were collected between 2014–2021 during three previous clinical trials related to MRS muscle metabolomics at the UW Department of Radiology [ 31 , 32 , 33 ].…”

Section: Methodsmentioning

confidence: 99%

ATP and NAD+ Deficiency in Parkinson’s Disease

et al. 2023

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The goal of this study is to identify a signature of bioenergetic and functional markers in the muscles of individuals with Parkinson’s disease (PD). Quantitative physiological properties of in vivo hand muscle (FDI, first dorsal interosseus) and leg muscle (TA, Tibialis Anterior) of older individuals with PD were compared to historical age/gender-matched controls (N = 30). Magnetic resonance spectroscopy and imaging (MRS) were used to assess in vivo mitochondrial and cell energetic dysfunction, including maximum mitochondrial ATP production (ATPmax), NAD concentrations linked to energy/stress pathways, and muscle size. Muscle function was measured via a single muscle fatigue test. TA ATPmax and NAD levels were significantly lower in the PD cohort compared to controls (ATPmax: 0.66 mM/s ± 0.03 vs. 0.76 ± 0.02; NAD: 0.75 mM ± 0.05 vs. 0.91 ± 0.04). Muscle endurance and specific force were also lower in both hand and leg muscles in the PD subjects. Exploratory analyses of mitochondrial markers and individual symptoms suggested that higher ATPmax was associated with a greater sense of motivation and engagement and less REM sleep behavior disorder (RBD). ATPmax was not associated with clinical severity or individual symptom(s), years since diagnosis, or quality of life. Results from this pilot study contribute to a growing body of evidence that PD is not a brain disease, but a systemic metabolic syndrome with disrupted cellular energetics and function in peripheral tissues. The significant impairment of both mitochondrial ATP production and resting metabolite levels in the TA muscles of the PD patients suggests that skeletal muscle mitochondrial function may be an important tool for mechanistic understanding and clinical application in PD patients. This study looked at individuals with mid-stage PD; future research should evaluate whether the observed metabolic perturbations in muscle dysfunction occur in the early stages of the disease and whether they have value as theragnostic biomarkers.

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“…Animal studies have demonstrated the ability of SS-31 to maintain cellular bioenergetics under stress conditions such as ischemia, hypoxia, and aging-related dysfunction ( Allen et al, 2020 ; Campbell et al, 2019 ; Szeto, 2018 ; Zhang et al, 2020 ). The clinical efficacy of SS-31 has been demonstrated for primary mitochondrial disorders ( Zhao et al, 2017 ; Reid Thompson et al, 2021 ) and for age-related chronic diseases associated with mitochondrial dysfunction ( Roshanravan et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds

Mitchell

Tamucci

et al. 2022

eLife

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Mitochondria play a central role in metabolic homeostasis, and dysfunction of this organelle underpins the etiology of many heritable and aging-related diseases. Tetrapeptides with alternating cationic and aromatic residues such as SS-31 (elamipretide) show promise as therapeutic compounds for mitochondrial disorders. In this study, we conducted a quantitative structure-activity analysis of three alternative tetrapeptide analogs, benchmarked against SS-31, that differ with respect to aromatic side chain composition and sequence register. We present the first structural models for this class of compounds, obtained with Nuclear Magnetic Resonance (NMR) and molecular dynamics approaches, showing that all analogs except for SS-31 form compact reverse turn conformations in the membrane-bound state. All peptide analogs bound cardiolipin-containing membranes, yet they had significant differences in equilibrium binding behavior and membrane interactions. Notably, analogs had markedly different effects on membrane surface charge, supporting a mechanism in which modulation of membrane electrostatics is a key feature of their mechanism of action. The peptides had no strict requirement for side chain composition or sequence register to permeate cells and target mitochondria in mammalian cell culture assays. All four peptides were pharmacologically active in serum withdrawal cell stress models yet showed significant differences in their abilities to restore mitochondrial membrane potential, preserve ATP content, and promote cell survival. Within our peptide set, the analog containing tryptophan side chains, SPN10, had the strongest impact on most membrane properties and showed greatest efficacy in cell culture studies. Taken together, these results show that side chain composition and register influence the activity of these mitochondria-targeted peptides, helping provide a framework for the rational design of next-generation therapeutics with enhanced potency.

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In vivo mitochondrial ATP production is improved in older adult skeletal muscle after a single dose of elamipretide in a randomized trial

Cited by 28 publications

References 46 publications

Long-term treatment with Elamipretide enhances healthy aging phenotypes in mice

Long-term treatment with Elamipretide enhances healthy aging phenotypes in mice

ATP and NAD+ Deficiency in Parkinson’s Disease

Structure-activity relationships of mitochondria-targeted tetrapeptide pharmacological compounds

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