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Targeting Mitochondrial Free Radical Production to Improve Aged Skeletal Muscle Function Disclosure: Paid consultant for Stealth Biotherapeutics David.

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Presentation on theme: "Targeting Mitochondrial Free Radical Production to Improve Aged Skeletal Muscle Function Disclosure: Paid consultant for Stealth Biotherapeutics David."— Presentation transcript:

1 Targeting Mitochondrial Free Radical Production to Improve Aged Skeletal Muscle Function Disclosure: Paid consultant for Stealth Biotherapeutics David Marcinek Department of Radiology University of Washington Muscle Study Group Buffalo, NY September 23, 2014

2 Marriotto; Liao; NIDDK.

3 Multifactorial Origins of Sarcopenia Oxidative Damage Reduced Physical Activity Decreased Anabolic Hormones Mitochondrial Dysfunction Inflammation Reduced Satellite Cell Function Neuromuscular Junction Defects ?

4 STRUCTURAL CHANGES Irreversible (carbonyls, HNE, …) mtDNA mutations OXIDATIVE DAMAGE MITOCHONDRIAL DEFECTS Intrinsic to mitochondria MUSCLE DYSFUNCTION REDOX STRESS REDOX SIGNALING Reversible redox modification Morphology INHIBITION Intact system Homeostasis Redox signaling (adaptive) Redox Stress (inhibition) Oxidative Damage HEALTHDISEASE OXIDATIVE STRESS Marcinek and Siegel. Aging. 2013

5 UCP3 H+ Redox control of mitochondrial proteins Mailloux et al., JBC Garcia et al., JBC McLain et al., Free Radic Res Taylor et al., JBC Fratelli et al., PNAS Han et al., Biochem Odin et al., J Clin Invest Aon et al., Biochim Biophys Acta. 2010

6 In Vivo Metabolic Spectroscopy Siegel et al., (2012) Mech Ageing Dev Optical Spectroscopy: O 2 cons. MR Spectroscopy: ATP prod. Hindlimb Optics Cuff MR Coil

7 ATP Metabolic Spectroscopy MbO 2 HbO 2 PCr CK Metabolic Spectroscopy Optical Spectra 31 P NMR

8 Parallel effects of ox. stress and aging on in vivo energetics # * Siegel et al. Mech Age Devel # * *

9 Aging In Vivo Energetics Similar in Mice and Humans Conley et al. J Physiol QUAD Amara et al. PNAS FDI

10 Summary 1.Age-related mito deficits similar in mice and elderly humans 2.Induced oxidative stress similar to age- related deficits Acute manipulation of oxidative stress will reverse mito deficits in aged muscle. Hypothesis

11 Szeto, et al. Antiox and Redox Sig., 2008 Anderson, et al., J Clin Invest Mitochondrial-targeted peptide Bendavia (SS-31) Zhao, et al., JBC. 2004

12 Bendavia interacts with cardiolipin (CL) Birk et al. JASN CL interacts with each ETC complex Necessary for cristae structure Anchors supercomplexes Preferentially oxidized by stress and disease MLCL + SS-31 POPC TLCLMLCL SS-31

13 H 2 O 2 Production Bendavia (SS-31) Mitochondrial H 2 O 2 Production

14 Bendavia Reverses In Vivo Mitochondrial Deficits Siegel et al., Aging Cell Inject young and old mice with 3mg/kg SS-31 (~2μM) → in vivo spectroscopy 1 hour later (5 mo) (27 mo)

15 Inject young and old mice with 3mg/kg SS-31 (~2μM) → in vivo spectroscopy 1 hour later Siegel et al., Aging Cell Bendavia Reverses In Vivo Mitochondrial Deficits

16 Siegel et al., Aging Cell. (2013) Bendavia GSH redox state in aged muscle

17 Function? Does reversal of mitochondrial deficits translate to improved skeletal muscle performance? Summary 1. Reduces mito H 2 O 2 – not a scavenger. 2. Acute Bendavia reverses mito deficits. 3. Does not effect healthy mito function

18 Improved muscle performance 1 hr after single 3 mg/kg young Siegel et al., Aging Cell and unpublished *

19 Improved Exercise Capacity in Old Mice 7 daily 3 mg/kg doses OLD (26 mo) YOUNG (6 mo)

20 Improved Exercise Capacity with 4 week Bendavia Male 6 mo 25 mo Female 6 mo27 mo

21 Take Home Messages 1.Mitochondrial redox environment controls in vivo energetics and function in aging skeletal muscle 2.Bendavia represents a new class of compound to target mitochondrial oxidative stress. 3.Acute Bendavia improves age-related skeletal muscle function and exercise tolerance.

22 Phase IIa test of acute Bendavia PI – Baback Roshanravan, MD (UW) Coord-Inv – Kevin Conley, PhD (UW) (SPITM-201) 1.Randomized, double-blind, placebo-controlled 2.Single dose, pre, post measurements 3.Target n=20 per group 4.Muscle function, in vivo energetics

23 Collaborators Wei Jun Qian (PNNL) Justin Percival (UW) Terry Kavanagh (UW) Collin White (UW) Dave Brown (ECU) Hazel Szeto (Cornel) Stealth Biotherapeutics Acknowledgements Marcinek Lab Michael Siegel (OHSU) Shane Kruse Matt Campbell Rudy Stuppard Gary Knowels Preston Kendrick UW Nathan Shock Center Peter Rabinovitch Ann Chiao Pabalu Karunadharma Nate Basisty Mike MacCoss Lab Website:

24

25 Effect on Thiol Redox Status Sohal and Orr. Free Rad Biol Med. 2012

26 Thiol oxidation: with age, with Bendavia (4wk) Increased S-glut with age Partial reversal with SS-31

27 Thiol oxidation: with age, with Bendavia (SS-31, 4wk)

28 Take Home Messages 1.Bendavia improves mitochondrial function and exercise tolerance. 2.Bendavia restores redox homeostasis as well as energy homeostasis. 3.Restoring redox homeostasis can effect cell physiology through the thiol proteome in addition to directly improving energetics.

29 NAD + H + H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ H+H+ Proton Motive Force (predominantly  m ) H+H+ Mitochondrial Matrix Cardiolipin Peroxidized Cardiolipin Reactive Oxygen Species (ROS) Bendavia Physiological Mitochondrial Respiration Pathological Mitochondrial Respiration Oxygen

30 Parallel effects of PQ and aging on skeletal muscle energetics # * * # * In Vivo Maximum (state 3) Proton leak (state 4) Ex Vivo perm fibers Siegel et al. Mech Age Devel. 2012


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