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Ectopic catalase expression in mitochondria by adeno-associated virus enhances exercise performance in mice.

Li D, Lai Y, Yue Y, Rabinovitch PS, Hakim C, Duan D - PLoS ONE (2009)

Bottom Line: However, administration of generic antioxidants has failed to convincingly improve performance during exhaustive exercise.Our result provides a framework for further elucidating the underlying mechanism.It also raises the hope of applying similar strategies to remove excessive, pathogenic free radicals in certain muscle diseases (such as Duchenne muscular dystrophy) and ameliorate muscle disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA.

ABSTRACT
Oxidative stress is thought to compromise muscle contractility. However, administration of generic antioxidants has failed to convincingly improve performance during exhaustive exercise. One possible explanation may relate to the inability of the supplemented antioxidants to effectively eliminate excessive free radicals at the site of generation. Here, we tested whether delivering catalase to the mitochondria, a site of free radical production in contracting muscle, could improve treadmill performance in C57Bl/6 mice. Recombinant adeno-associated virus serotype-9 (AV.RSV.MCAT) was generated to express a mitochondria-targeted catalase gene. AV.RSV.MCAT was delivered to newborn C57Bl/6 mouse circulation at the dose of 10(12) vector genome particles per mouse. Three months later, we observed a approximately 2 to 10-fold increase of catalase protein and activity in skeletal muscle and the heart. Subcellular fractionation western blot and double immunofluorescence staining confirmed ectopic catalase expression in the mitochondria. Compared with untreated control mice, absolute running distance and body weight normalized running distance were significantly improved in AV.RSV.MCAT infected mice during exhaustive treadmill running. Interestingly, ex vivo contractility of the extensor digitorum longus muscle was not altered. Taken together, we have demonstrated that forced catalase expression in the mitochondria enhances exercise performance. Our result provides a framework for further elucidating the underlying mechanism. It also raises the hope of applying similar strategies to remove excessive, pathogenic free radicals in certain muscle diseases (such as Duchenne muscular dystrophy) and ameliorate muscle disease.

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The contractility of the isolated EDL muscle is not altered following systemic AV.RSV.MCAT infection.A to C, results from male mice; D to F, results from female mice. A and D, absolute twitch (left panel) and tetanic forces (right panels). B and E, cross-sectional area normalized specific twitch (left panel) and tetanic forces (right panels). C and F, fatigue response (left panel) and eccentric contraction profile (right panel). Filled bar/circle, AV.RSV.MCAT infected mice; Open bar/circle, uninfected mice.
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pone-0006673-g004: The contractility of the isolated EDL muscle is not altered following systemic AV.RSV.MCAT infection.A to C, results from male mice; D to F, results from female mice. A and D, absolute twitch (left panel) and tetanic forces (right panels). B and E, cross-sectional area normalized specific twitch (left panel) and tetanic forces (right panels). C and F, fatigue response (left panel) and eccentric contraction profile (right panel). Filled bar/circle, AV.RSV.MCAT infected mice; Open bar/circle, uninfected mice.

Mentions: We compared the anatomic and contractile properties of the freshly isolated EDL muscle. We did not see a significant difference in muscle weight, length and cross-sectional area between AV.RSV.MCAT infected and uninfected mice (Table 1). Specific and absolute muscle forces were not altered either (Figure 4).


Ectopic catalase expression in mitochondria by adeno-associated virus enhances exercise performance in mice.

Li D, Lai Y, Yue Y, Rabinovitch PS, Hakim C, Duan D - PLoS ONE (2009)

The contractility of the isolated EDL muscle is not altered following systemic AV.RSV.MCAT infection.A to C, results from male mice; D to F, results from female mice. A and D, absolute twitch (left panel) and tetanic forces (right panels). B and E, cross-sectional area normalized specific twitch (left panel) and tetanic forces (right panels). C and F, fatigue response (left panel) and eccentric contraction profile (right panel). Filled bar/circle, AV.RSV.MCAT infected mice; Open bar/circle, uninfected mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2723912&req=5

pone-0006673-g004: The contractility of the isolated EDL muscle is not altered following systemic AV.RSV.MCAT infection.A to C, results from male mice; D to F, results from female mice. A and D, absolute twitch (left panel) and tetanic forces (right panels). B and E, cross-sectional area normalized specific twitch (left panel) and tetanic forces (right panels). C and F, fatigue response (left panel) and eccentric contraction profile (right panel). Filled bar/circle, AV.RSV.MCAT infected mice; Open bar/circle, uninfected mice.
Mentions: We compared the anatomic and contractile properties of the freshly isolated EDL muscle. We did not see a significant difference in muscle weight, length and cross-sectional area between AV.RSV.MCAT infected and uninfected mice (Table 1). Specific and absolute muscle forces were not altered either (Figure 4).

Bottom Line: However, administration of generic antioxidants has failed to convincingly improve performance during exhaustive exercise.Our result provides a framework for further elucidating the underlying mechanism.It also raises the hope of applying similar strategies to remove excessive, pathogenic free radicals in certain muscle diseases (such as Duchenne muscular dystrophy) and ameliorate muscle disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Microbiology and Immunology, School of Medicine, University of Missouri, Columbia, MO, USA.

ABSTRACT
Oxidative stress is thought to compromise muscle contractility. However, administration of generic antioxidants has failed to convincingly improve performance during exhaustive exercise. One possible explanation may relate to the inability of the supplemented antioxidants to effectively eliminate excessive free radicals at the site of generation. Here, we tested whether delivering catalase to the mitochondria, a site of free radical production in contracting muscle, could improve treadmill performance in C57Bl/6 mice. Recombinant adeno-associated virus serotype-9 (AV.RSV.MCAT) was generated to express a mitochondria-targeted catalase gene. AV.RSV.MCAT was delivered to newborn C57Bl/6 mouse circulation at the dose of 10(12) vector genome particles per mouse. Three months later, we observed a approximately 2 to 10-fold increase of catalase protein and activity in skeletal muscle and the heart. Subcellular fractionation western blot and double immunofluorescence staining confirmed ectopic catalase expression in the mitochondria. Compared with untreated control mice, absolute running distance and body weight normalized running distance were significantly improved in AV.RSV.MCAT infected mice during exhaustive treadmill running. Interestingly, ex vivo contractility of the extensor digitorum longus muscle was not altered. Taken together, we have demonstrated that forced catalase expression in the mitochondria enhances exercise performance. Our result provides a framework for further elucidating the underlying mechanism. It also raises the hope of applying similar strategies to remove excessive, pathogenic free radicals in certain muscle diseases (such as Duchenne muscular dystrophy) and ameliorate muscle disease.

Show MeSH
Related in: MedlinePlus