Marcinek 2016 Abstract MitoFit Science Camp 2016
|Targeting mitochondrial redox stress reveals two phases for reversal of mitochondrial dysfunction in aged mouse skeletal muscle.
Mitochondrial oxidative stress is associated with many chronic diseases and age-related dysfunction. However, the mechanistic relationship between mitochondrial oxidative stress, mitochondrial function, and pathology remain poorly defined. The complex interactions between the mitochondria and cell environment make assessing their role in chronic disease difficult. This is particularly true in aging skeletal muscle, where transient periods of elevated oxidative stress are a normal part of the cellular response to muscle contraction. In this study we used the mitochondrial targeted peptide elamipretide (SS-31), which associates with cardiolipin (CL) on the inner mitochondrial membrane, to test the interaction between mitochondrial oxidative stress, energetics, and muscle performance in aged mice.
Young (5-7 months) and old (26-28 months) female C57Bl/6 mice were treated with either saline or 3 mg/kg/day SS-31. In the first experiment mice were treated with a single IP injection 1 hr before the assay. In the second experiment mice were treated for 8 weeks by continual infusion using osmotic minipumps. Following treatment mitochondrial function was measured in vivo using a combination of NMR and optical spectroscopy or with HRR in permeabilized EDL muscles. Muscle performance was assessed with electrical stimulation and treadmill endurance.
We observed age-related declines in the coupling of oxidative phosphorylation (reduced P/O) and maximum ATP production (ATPmax) in vivo that were partially reversed by both 1 hr and 8 weeks of SS-31 treatment. The improved energetics in both SS-31 treated groups was associated with elevated glutathione levels and greater fatigue resistance of the muscle. The 8-week treatment group also demonstrated less oxidative damage (lower HNE) and immature monolysocardiolipin. Surprisingly, neither the decline in ATPmax with age nor the improvements with SS-31 treatment were reflected in changes in state 3 respiration in permeabilized EDL muscle measured at 25 ⁰C. Further analyses demonstrated increased citrate synthase activity and ET-pathway protein expression in the gastrocnemius muscle of aged mice that was reversed after 8 weeks of SS-31. Treatment had no effect on energetics or markers of mitochondrial content in young muscle. Using ATPmax/CS activity as a measure of mitochondrial quality indicates reduced mitochondrial quality in aged muscle. This mitochondrial quality is partially improved within 1 hr of SS-31 treatment, while extended 8 week treatment further restores mitochondrial quality to near young levels.
Labels: MiParea: Respiration Pathology: Aging;senescence Stress:Oxidative stress;RONS Organism: Mouse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: OXPHOS
HRR: Oxygraph-2k Event: C1 MitoFit Science Camp 2016, Elamipretide
1-Dept Radiol, Univ Washington, Seattle, WA, USA; 2-Nat Psoriasis Foundation, Portland, OR, USA. - email@example.com
In conclusion our data indicate multiple levels of control of mitochondrial deficits by oxidative stress. Acute inhibition of mitochondria by oxidative stress is apparent in the rapid reversal of mitochondrial deficits after as little as 1 hr. The difference between in vivo and ex vivo results suggests that this level of control is dependent on the interaction between the cell environment and the mitochondria and may indicate reversible redox inhibition of mitochondrial function in vivo. This dynamic control is in addition to oxidative damage to structural components of the mitochondria reflected by further improvements in function following 8 weeks of treatment. These results suggest that direct targeting of the mitochondrial redox environment is a promising strategy to reverse dysfunction in chronic disease.
- Siegel MP, Kruse SE, Percival JM, Goh J, White CC, Hopkins HC, Kavanagh TJ, Szeto HH, Rabinovitch PS, and Marcinek DJ (2013) Mitochondrial-targeted peptide rapidly improves mitochondrial energetics and skeletal muscle performance in aged mice. Aging Cell 12:763-71.