title: Cardiac myostatin upregulation occurs immediately after myocardial ischemia and is involved in skeletal muscle activation of atrophy.
abstract: Myostatin (MSTN), a negative regulator of muscle growth and size, is increased after acute myocardial infarction (AMI) but timing of upregulation after injury is not known. In this study, we investigated the timing of the MSTN/AKT/p38 pathway activation in heart and skeletal muscle after AMI, as well as the potential effect of cardiac injury-related MSTN endocrine signaling on skeletal muscle and other circulating growth factors.
  
  
  METHODS
  Coronary artery ligation was performed in C57BL/6 mice at age 8 weeks to induce AMI. Mice were sacrificed at different time points (10 m, 1 h, 2 h, 6 h, 12 h, 24 h, 1 week, 2 weeks, 1 months and 2 months) after surgery (n=3 per time point, n=18 total).
  
  
  RESULTS
  Cardiac and circulating MSTN upregulation occurred as early as 10 min after AMI. Two months after AMI, increased cardiac MSTN/SMAD2,3 and p38 together with decreased IGF-1/AKT signaling suggest an anti-hypertrophic profile. In skeletal muscle, an absence of local MSTN increase was accompanied by increased MSTN-dependent SMAD2,3 signaling, suggestive of paracrine effects due to cardiac-derived MSTN. Protein degradation by the ubiquitin-proteasome system in the skeletal muscle was also evident. Serum from 24h post-MI mice effectively induced a MSTN-dependent increase in atrogin1 and MuRF1.
  
  
  CONCLUSIONS
  Our study shows that cardiac MTSN activation occurs rapidly after cardiac ischemia and may be involved in peripheral protein degradation in the skeletal muscle by activating atrogin1 and MuRF1.
authors.affiliation: Division of Cardiothoracic Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, United States.
authors.forename: Estibaliz
authors.initials: E
authors.lastname: Castillero
authors.affiliation: Department of Cardiovascular Surgery, Juntendo University, Tokyo, Japan.
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Akashi
authors.affiliation: Division of Cardiothoracic Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, United States.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wang
authors.affiliation: Division of Cardiothoracic Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, United States.
authors.forename: Marc
authors.initials: M
authors.lastname: Najjar
authors.affiliation: Division of Cardiology, College of Physicians and Surgeons of Columbia University, New York, NY, United States.
authors.forename: Ruiping
authors.initials: R
authors.lastname: Ji
authors.affiliation: Division of Cardiology, College of Physicians and Surgeons of Columbia University, New York, NY, United States.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Kennel
authors.affiliation: Department of Physiology, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: H Lee
authors.initials: HL
authors.lastname: Sweeney
authors.affiliation: Division of Cardiology, College of Physicians and Surgeons of Columbia University, New York, NY, United States.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Schulze
authors.affiliation: Division of Cardiothoracic Surgery, College of Physicians and Surgeons of Columbia University, New York, NY, United States. Electronic address: Ig2006@cumc.coumbia.edu.
authors.forename: Isaac
authors.initials: I
authors.lastname: George
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D017202:Myocardial Ischemia / Q000097:blood / Q000473:pathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D055435:Myostatin / Q000097:blood / Q000378:metabolism*; D044843:SKP Cullin F-Box Protein Ligases / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D013997:Time Factors; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C525912:Mstn protein, mouse; D009124:Muscle Proteins; D055435:Myostatin; D051785:Smad Proteins; D000070584:Tripartite Motif Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases
keywords: Cardiac cachexia; Grow factors; Heart failure; Ischemia; Myostatin