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      Novel Sarcopenia-related Alterations in Sarcomeric Protein Post-translational Modifications (PTMs) in Skeletal Muscles Identified by Top-down Proteomics.

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          Abstract

          Sarcopenia, the age-related loss of skeletal muscle mass and strength, is a significant cause of morbidity in the elderly and is a major burden on health care systems. Unfortunately, the underlying molecular mechanisms in sarcopenia remain poorly understood. Herein, we utilized top-down proteomics to elucidate sarcopenia-related changes in the fast- and slow-twitch skeletal muscles of aging rats with a focus on the sarcomeric proteome, which includes both myofilament and Z-disc proteins-the proteins that constitute the contractile apparatuses. Top-down quantitative proteomics identified significant changes in the post-translational modifications (PTMs) of critical myofilament proteins in the fast-twitch skeletal muscles of aging rats, in accordance with the vulnerability of fast-twitch muscles to sarcopenia. Surprisingly, age-related alterations in the phosphorylation of Cypher isoforms, proteins that localize to the Z-discs in striated muscles, were also noted in the fast-twitch skeletal muscle of aging rats. This represents the first report of changes in the phosphorylation of Z-disc proteins in skeletal muscle during aging. In addition, increased glutathionylation of slow skeletal troponin I, a novel modification that may help protect against oxidative damage, was observed in slow-twitch skeletal muscles. Furthermore, we have identified and characterized novel muscle type-specific proteoforms of myofilament proteins and Z-disc proteins, including a novel isoform of the Z-disc protein Enigma. The finding that the phosphorylation of Z-disc proteins is altered in response to aging in the fast-twitch skeletal muscles of aging rats opens new avenues for the investigation of the role of Z-discs in age-related muscle dysfunction.

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          Author and article information

          Journal
          Mol. Cell Proteomics
          Molecular & cellular proteomics : MCP
          American Society for Biochemistry & Molecular Biology (ASBMB)
          1535-9484
          1535-9476
          Jan 2018
          : 17
          : 1
          Affiliations
          [1 ] From the ‡Department of Cell and Regenerative Biology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53705.
          [2 ] §Institutes of Biomedical Sciences, Fudan University, Shanghai, 200032, P. R. China.
          [3 ] ¶Molecular and Cellular Pharmacology Training Program, University of Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53705.
          [4 ] ‖Human Proteomics Program,University of Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53705.
          [5 ] **Department of Chemistry, University of Wisconsin-Madison, 1101 University Ave., Madison, Wisconsin, 53706.
          [6 ] ‡‡Department of Kinesiology, University of Wisconsin-Madison, 2000 Observatory Dr., Madison, Wisconsin, 53705.
          [7 ] §§Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, 600 Highland Ave., Madison, Wisconsin, 53792.
          [8 ] ¶¶UW Carbone Cancer Center, University of Wisconsin-Madison, 600 Highland Ave., Madison, Wisconsin, 53792.
          [9 ] ‖‖Departments of Agriculture, Food, and Nutritional Sciences, University of Alberta-Edmonton, Edmonton, AB, Canada.
          [10 ] From the ‡Department of Cell and Regenerative Biology, University of Wisconsin-Madison, 1111 Highland Ave., Madison, Wisconsin, 53705; ge2@wisc.edu.
          Article
          RA117.000124
          10.1074/mcp.RA117.000124
          5750843
          29046390

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