Lang, Franziska, Aravamudhan, Sriram, Nolte, Hendrik, Tuerk, Clara, Hoelper, Soraya, Mueller, Stefan, Guenther, Stefan, Blaauw, Bert, Braun, Thomas ORCID: 0000-0002-6165-4804 and Krueger, Marcus (2017). Dynamic changes in the mouse skeletal muscle proteome during denervation-induced atrophy. Dis. Model. Mech., 10 (7). S. 881 - 897. CAMBRIDGE: COMPANY BIOLOGISTS LTD. ISSN 1754-8411

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Abstract

Loss of neuronal stimulation enhances protein breakdown and reduces protein synthesis, causing rapid loss of muscle mass. To elucidate the pathophysiological adaptations that occur in atrophying muscles, we used stable isotope labelling and mass spectrometry to quantify protein expression changes accurately during denervation-induced atrophy after sciatic nerve section in the mouse gastrocnemius muscle. Additionally, mice were fed a stable isotope labelling of amino acids in cell culture (SILAC) diet containing C-13(6)-lysine for 4, 7 or 11 days to calculate relative levels of protein synthesis in denervated and control muscles. Ubiquitin remnant peptides (K-epsilon-GG) were profiled by immunoaffinity enrichment to identify potential substrates of the ubiquitin-proteasomal pathway. Of the 4279 skeletal muscle proteins quantified, 850 were differentially expressed significantly within 2 weeks after denervation compared with control muscles. Moreover, pulse labelling identified Lys6 incorporation in 4786 proteins, of which 43 had differential Lys6 incorporation between control and denervated muscle. Enrichment of diglycine remnants identified 2100 endogenous ubiquitination sites and revealed a metabolic and myofibrillar protein diglycine signature, including myosin heavy chains, myomesins and titin, during denervation. Comparative analysis of these proteomic data sets with known atrogenes using a random forest approach identified 92 proteins subject to atrogene-like regulation that have not previously been associated directly with denervation-induced atrophy. Comparison of protein synthesis and proteomic data indicated that upregulation of specific proteins in response to denervation is mainly achieved by protein stabilization. This study provides the first integrated analysis of protein expression, synthesis and ubiquitin signatures during muscular atrophy in a living animal.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Lang, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Aravamudhan, SriramUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nolte, HendrikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Tuerk, ClaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoelper, SorayaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mueller, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Guenther, StefanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Blaauw, BertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Braun, ThomasUNSPECIFIEDorcid.org/0000-0002-6165-4804UNSPECIFIED
Krueger, MarcusUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-226577
DOI: 10.1242/dmm.028910
Journal or Publication Title: Dis. Model. Mech.
Volume: 10
Number: 7
Page Range: S. 881 - 897
Date: 2017
Publisher: COMPANY BIOLOGISTS LTD
Place of Publication: CAMBRIDGE
ISSN: 1754-8411
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
M-BAND; OXIDATIVE STRESS; UBIQUITIN LIGASE; MOLECULAR-BASIS; EXPRESSION; IDENTIFICATION; PROTEASOME; BINDING; SILAC; GENEMultiple languages
Cell Biology; PathologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22657

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