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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 G; Szeto, Hazel H; Rabinovitch, Peter S; MacCoss, Michael J; Qian, Wei-Jun; Marcinek, David J.
Afiliación
  • Campbell MD; Department of Radiology, University of Washington, Seattle, WA, USA. Electronic address: mdcampbe@uw.edu.
  • Duan J; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA. Electronic address: jicheng.duan@bioverativ.com.
  • Samuelson AT; Department of Radiology, University of Washington, Seattle, WA, USA. Electronic address: ats95@uw.edu.
  • Gaffrey MJ; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA. Electronic address: Matthew.Gaffrey@pnnl.gov.
  • Merrihew GE; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Electronic address: genn@uw.edu.
  • Egertson JD; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Electronic address: jegertso@uw.edu.
  • Wang L; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA. Electronic address: lwang3@uw.edu.
  • Bammler TK; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA. Electronic address: tbammler@uw.edu.
  • Moore RJ; Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA, USA. Electronic address: ronald.moore@pnnl.gov.
  • White CC; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA. Electronic address: ccwhite@uw.edu.
  • Kavanagh TJ; Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA. Electronic address: tjkav@uw.edu.
  • Voss JG; School of Nursing, University of Washington, Seattle, WA, USA. Electronic address: jgv20@case.edu.
  • Szeto HH; Social Profit Network, Menlo Park, CA, USA.
  • Rabinovitch PS; Department of Pathology, University of Washington, Seattle, WA, USA. Electronic address: petersr@uw.edu.
  • MacCoss MJ; Department of Genome Sciences, University of Washington, Seattle, WA, USA. Electronic address: maccoss@uw.edu.
  • Qian WJ; School of Nursing, University of Washington, Seattle, WA, USA. Electronic address: Weijun.Qian@pnnl.gov.
  • Marcinek DJ; Department of Radiology, University of Washington, Seattle, WA, USA. Electronic address: dmarc@uw.edu.
Free Radic Biol Med ; 134: 268-281, 2019 04.
Article en En | MEDLINE | ID: mdl-30597195
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Condicionamiento Físico Animal / Envejecimiento / Tolerancia al Ejercicio / Estrés Oxidativo / Músculo Esquelético / Mitocondrias Aspecto: Patient_preference Límite: Animals Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Oligopéptidos / Condicionamiento Físico Animal / Envejecimiento / Tolerancia al Ejercicio / Estrés Oxidativo / Músculo Esquelético / Mitocondrias Aspecto: Patient_preference Límite: Animals Idioma: En Revista: Free Radic Biol Med Asunto de la revista: BIOQUIMICA / MEDICINA Año: 2019 Tipo del documento: Article Pais de publicación: Estados Unidos