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      Antioxidant Treatment Reduces Formation of Structural Cores and Improves Muscle Function in RYR1 Y522S/WT Mice


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          Central core disease (CCD) is a congenital myopathy linked to mutations in the ryanodine receptor type 1 (RYR1), the sarcoplasmic reticulum Ca 2+ release channel of skeletal muscle. CCD is characterized by formation of amorphous cores within muscle fibers, lacking mitochondrial activity. In skeletal muscle of RYR1 Y522S/WT knock-in mice, carrying a human mutation in RYR1 linked to malignant hyperthermia (MH) with cores, oxidative stress is elevated and fibers present severe mitochondrial damage and cores. We treated RYR1 Y522S/WT mice with N-acetylcysteine (NAC), an antioxidant provided ad libitum in drinking water for either 2 or 6 months. Our results show that 2 months of NAC treatment starting at 2 months of age, when mitochondrial and fiber damage was still minimal, (i) reduce formation of unstructured and contracture cores, (ii) improve muscle function, and (iii) decrease mitochondrial damage. The beneficial effect of NAC treatment is also evident following 6 months of treatment starting at 4 months of age, when structural damage was at an advanced stage. NAC exerts its protective effect likely by lowering oxidative stress, as supported by the reduction of 3-NT and SOD2 levels. This work suggests that NAC administration is beneficial to prevent mitochondrial damage and formation of cores and improve muscle function in RYR1 Y522S/WT mice.

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          Most cited references65

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          The calpain system.

          The calpain system originally comprised three molecules: two Ca2+-dependent proteases, mu-calpain and m-calpain, and a third polypeptide, calpastatin, whose only known function is to inhibit the two calpains. Both mu- and m-calpain are heterodimers containing an identical 28-kDa subunit and an 80-kDa subunit that shares 55-65% sequence homology between the two proteases. The crystallographic structure of m-calpain reveals six "domains" in the 80-kDa subunit: 1). a 19-amino acid NH2-terminal sequence; 2). and 3). two domains that constitute the active site, IIa and IIb; 4). domain III; 5). an 18-amino acid extended sequence linking domain III to domain IV; and 6). domain IV, which resembles the penta EF-hand family of polypeptides. The single calpastatin gene can produce eight or more calpastatin polypeptides ranging from 17 to 85 kDa by use of different promoters and alternative splicing events. The physiological significance of these different calpastatins is unclear, although all bind to three different places on the calpain molecule; binding to at least two of the sites is Ca2+ dependent. Since 1989, cDNA cloning has identified 12 additional mRNAs in mammals that encode polypeptides homologous to domains IIa and IIb of the 80-kDa subunit of mu- and m-calpain, and calpain-like mRNAs have been identified in other organisms. The molecules encoded by these mRNAs have not been isolated, so little is known about their properties. How calpain activity is regulated in cells is still unclear, but the calpains ostensibly participate in a variety of cellular processes including remodeling of cytoskeletal/membrane attachments, different signal transduction pathways, and apoptosis. Deregulated calpain activity following loss of Ca2+ homeostasis results in tissue damage in response to events such as myocardial infarcts, stroke, and brain trauma.
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            Oxidative damage to proteins: spectrophotometric method for carbonyl assay.

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              Biochemical markers of muscular damage.

              Muscle tissue may be damaged following intense prolonged training as a consequence of both metabolic and mechanical factors. Serum levels of skeletal muscle enzymes or proteins are markers of the functional status of muscle tissue, and vary widely in both pathological and physiological conditions. Creatine kinase, lactate dehydrogenase, aldolase, myoglobin, troponin, aspartate aminotransferase, and carbonic anhydrase CAIII are the most useful serum markers of muscle injury, but apoptosis in muscle tissues subsequent to strenuous exercise may be also triggered by increased oxidative stress. Therefore, total antioxidant status can be used to evaluate the level of stress in muscle by other markers, such as thiobarbituric acid-reactive substances, malondialdehyde, sulfhydril groups, reduced glutathione, oxidized glutathione, superoxide dismutase, catalase and others. As the various markers provide a composite picture of muscle status, we recommend using more than one to provide a better estimation of muscle stress.

                Author and article information

                Oxid Med Cell Longev
                Oxid Med Cell Longev
                Oxidative Medicine and Cellular Longevity
                10 September 2017
                : 2017
                1Center for Research on Aging and Translational Medicine (CeSI-MeT), University G. d'Annunzio of Chieti, 66100 Chieti, Italy
                2Department of Neuroscience, Imaging, and Clinical Sciences (DNICS), University G. d'Annunzio of Chieti, 66100 Chieti, Italy
                3Department of General Pathology, University Estadual de Londrina, 86057-970 Londrina, PR, Brazil
                4Department of Medicine and Aging Science (DMSI), University G. d'Annunzio of Chieti, 66100 Chieti, Italy
                Author notes

                Academic Editor: Marko D. Prokić

                Copyright © 2017 Antonio Michelucci et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: Italian Telethon ONLUS Foundation
                Award ID: GGP13213
                Funded by: Italian Ministry of Education, University and Research
                Award ID: RBFR13A20K
                Funded by: Italian Ministry of Health
                Award ID: GR-2011-02352681
                Funded by: National Institutes of Health
                Award ID: AR053349-06
                Research Article

                Molecular medicine
                Molecular medicine


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