title: Genetically enhancing mitochondrial antioxidant activity improves muscle function in aging.
abstract: Age-related skeletal muscle dysfunction is a leading cause of morbidity that affects up to half the population aged 80 or greater. Here we tested the effects of increased mitochondrial antioxidant activity on age-dependent skeletal muscle dysfunction using transgenic mice with targeted overexpression of the human catalase gene to mitochondria (MCat mice). Aged MCat mice exhibited improved voluntary exercise, increased skeletal muscle specific force and tetanic Ca(2+) transients, decreased intracellular Ca(2+) leak and increased sarcoplasmic reticulum (SR) Ca(2+) load compared with age-matched wild type (WT) littermates. Furthermore, ryanodine receptor 1 (the sarcoplasmic reticulum Ca(2+) release channel required for skeletal muscle contraction; RyR1) from aged MCat mice was less oxidized, depleted of the channel stabilizing subunit, calstabin1, and displayed increased single channel open probability (Po). Overall, these data indicate a direct role for mitochondrial free radicals in promoting the pathological intracellular Ca(2+) leak that underlies age-dependent loss of skeletal muscle function. This study harbors implications for the development of novel therapeutic strategies, including mitochondria-targeted antioxidants for treatment of mitochondrial myopathies and other healthspan-limiting disorders.
authors.affiliation: Department of Physiology and Cellular Biophysics, The Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and.
authors.forename: Alisa
authors.initials: A
authors.lastname: Umanskaya
authors.affiliation: Department of Physiology and Cellular Biophysics, The Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Santulli
authors.affiliation: Department of Physiology and Cellular Biophysics, The Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and.
authors.forename: Wenjun
authors.identifier: http://orcid.org/0000-0003-0493-062X
authors.initials: W
authors.lastname: Xie
authors.affiliation: Department of Physiology and Cellular Biophysics, The Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and.
authors.forename: Daniel C
authors.initials: DC
authors.lastname: Andersson
authors.affiliation: Department of Physiology and Cellular Biophysics, The Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and.
authors.forename: Steven R
authors.initials: SR
authors.lastname: Reiken
authors.affiliation: Department of Physiology and Cellular Biophysics, The Clyde and Helen Wu Center for Molecular Cardiology, Columbia University College of Physicians and Surgeons, New York, NY 10032; and Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032 arm42@columbia.edu.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Marks
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000375:Aging; D000818:Animals; D000975:Antioxidants / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002374:Catalase / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D046529:Microscopy, Electron, Transmission; D008928:Mitochondria / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology*; D010100:Oxygen / Q000378:metabolism; D011788:Quality of Life; D017382:Reactive Oxygen Species / Q000378:metabolism; D019837:Ryanodine Receptor Calcium Release Channel / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013314:Stress, Mechanical; D022061:Tacrolimus Binding Protein 1A / Q000378:metabolism; D013997:Time Factors
chemical_list: D000975:Antioxidants; D017382:Reactive Oxygen Species; D019837:Ryanodine Receptor Calcium Release Channel; C000592747:ryanodine receptor 1, mouse; D000255:Adenosine Triphosphate; D002374:Catalase; D022061:Tacrolimus Binding Protein 1A; D010100:Oxygen; D002118:Calcium
keywords: aging; exercise capacity; muscle weakness; oxidation; skeletal muscle