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

Journal Article · Tue Apr 30 04:00:00 EDT 2019 · Free Radical Biology & Medicine

DOI:https://doi.org/10.1016/j.freeradbiomed.2018.12.031· OSTI ID:1558399

Campbell, Mathew D. ^[1]; Duan, Jicheng ^[2]; Samuelson, Ashton T. ^[1]; Gaffrey, Matthew J. ^[2]; Merrihew, Gennifer E. ^[1]; Egertson, Jarrett D. ^[1]; Wang, Lu ^[1]; Bammler, Theo ^[3]; Moore, Ronald J. ^[2]; White, Collin C. ^[4]; Kavanagh, Terrance J. ^[4]; Voss, Joachim G. ^[1]; Szeto, Hazel H. ^[5]; Rabinovitch, Peter S. ^[1]; Maccoss, Michael J. ^[3]; Qian, Weijun ^[2]; Marcinek, David J. ^[1]

---

1. University of Washington
2. BATTELLE (PACIFIC NW LAB)
3. UNIVERSITY OF WASHINGTON
4. Washington State University
5. Social Profit Network

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.

• Research Organization: Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
• Sponsoring Organization: USDOE
• DOE Contract Number: AC05-76RL01830
• OSTI ID: 1558399
• Report Number(s): PNNL-SA-140379
• Journal Information: Free Radical Biology & Medicine, Journal Name: Free Radical Biology & Medicine Vol. 134
• Country of Publication: United States
• Language: English

Related Subjects

aging
fatigue
mitochondria
oxidative stress
skeletal muscle