title: Measurement of a MMP-2 degraded Titin fragment in serum reflects changes in muscle turnover induced by atrophy.
abstract: OBJECTIVE
  In this study we sought to determine whether a Titin peptide fragment can serve as a clinical biomarker for changes in muscle mass.
  
  
  METHODS
  Mass spectrometry was used to identify Titin fragment in urine. An antibody against this Titin sequence was raised and used to develop a competitive ELISA assay for measurement in serum. Rat tissue extractions in the presence or absence of a series of proteases of interest were used to identify its enzymatic origin. A rat model of dexamethasone (DEX) induced muscle atrophy and a human 56-day bed rest study with and without vibration therapy were used to assess biological and clinical relevance.
  
  
  RESULTS
  A technically robust ELISA measuring the Titin fragment was developed against a Titin peptide fragment identified in human urine. The fragment was shown to be produced primarily by MMP-2 cleavage of Titin. In the rat muscle DEX induced atrophy model, Titin-MMP2 fragment was decreased in the beginning of DEX treatment, and then significantly increased later on during DEX administration. In the human bed rest study, the Titin-MMP2 fragment was initially decreased 11.9 (±3.7) % after 1day of bed rest, and then gradually increased ending up at a 16.4 (±4.6) % increase at day 47.
  
  
  CONCLUSIONS
  We developed a robust ELISA measuring a muscle derived MMP-2 generated Titin degradation fragment in rat and human serum. Importantly, the fragment can be measured in serum and that these levels are related to induction of skeletal muscle atrophy.
authors: Nordic Bioscience Biomarkers and Research, Herlev, Denmark. Electronic address: ssu@nordicbioscience.com.
authors: S
authors: S
authors: Sun
authors: Nordic Bioscience Biomarkers and Research, Herlev, Denmark.
authors: K
authors: K
authors: Henriksen
authors: Nordic Bioscience Biomarkers and Research, Herlev, Denmark.
authors: M A
authors: MA
authors: Karsdal
authors: Center for Muscle and Bone Research, Charite Campus Benjamin Franklin, Free University and Humboldt-University Berlin, Berlin, Germany.
authors: G
authors: G
authors: Armbrecht
authors: Center for Muscle and Bone Research, Charite Campus Benjamin Franklin, Free University and Humboldt-University Berlin, Berlin, Germany.
authors: D L
authors: DL
authors: Belavý
authors: Center for Muscle and Bone Research, Charite Campus Benjamin Franklin, Free University and Humboldt-University Berlin, Berlin, Germany.
authors: D
authors: D
authors: Felsenberg
authors: Institute of Aerospace Medicine, German Aerospace Center (DLR), Cologne, Germany.
authors: J
authors: J
authors: Rittweger
authors: Nordic Bioscience Biomarkers and Research, Beijing, China.
authors: Y
authors: Y
authors: Wang
authors: Nordic Bioscience Biomarkers and Research, Beijing, China.
authors: Q
authors: Q
authors: Zheng
authors: Nordic Bioscience Biomarkers and Research, Herlev, Denmark; Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark.
authors: A F
authors: AF
authors: Nedergaard
mesh_terms: D000818:Animals; D001510:Bed Rest / Q000009:adverse effects; D015415:Biomarkers / Q000097:blood; D064211:Connectin / Q000097:blood*; D003907:Dexamethasone; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000473:pathology; D009133:Muscular Atrophy / Q000097:blood / Q000201:enzymology* / Q000209:etiology / Q000473:pathology / Q000517:prevention & control; D010446:Peptide Fragments / Q000097:blood*; D011237:Predictive Value of Tests; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014732:Vibration / Q000627:therapeutic use
chemical_list: D015415:Biomarkers; D064211:Connectin; D010446:Peptide Fragments; C577285:TTN protein, human; C577295:Ttn protein, rat; D003907:Dexamethasone; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat
keywords: Bed rest; Dexamethasone; MMP-2; Muscle atrophy; Titin