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Heart, Lung and Circulation
Original Article| Volume 27, ISSUE 6, P693-701, June 2018

Absence of Myostatin Improves Cardiac Function Following Myocardial Infarction

      Background

      Myostatin inhibits the development of skeletal muscle and regulates the proliferation of skeletal muscle fibroblasts. However, the role of myostatin in regulating cardiac muscle or myofibroblasts, specifically in acute myocardial infarction (MI), is less clear. This study sought to determine whether absence of myostatin altered left ventricular function post-MI.

      Methods

      Myostatin-null mice (Mstn−/−) and wild-type (WT) mice underwent ligation of the left anterior descending artery to induce MI. Left ventricular function was measured at baseline, days 1 and 28 post-MI. Immunohistochemistry and immunofluorescence were obtained at day 28 for cellular proliferation, collagen deposition, and myofibroblastic activity.

      Results

      Whilst left ventricular function at baseline and size of infarct were similar, significant differences in favour of Mstn−/− compared to WT mice post-MI include a greater recovery of ejection fraction (61.8 ± 1.1% vs 57.1 ± 2.3%, p< 0.01), less collagen deposition (41.9 ± 2.8% vs 54.7 ± 3.4%, p< 0.05), and lower mortality (0 vs. 20%, p< 0.05). There was no difference in the number of BrdU positive cells, percentage of apoptotic cardiomyocytes, or size of cardiomyocytes post-MI between WT and Mstn−/− mice.

      Conclusions

      Absence of myostatin potentially protects the function of the heart post-MI with improved survival, possibly by limiting extent of fibrosis.

      Keywords

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      References

        • McPherron A.C.
        • Lawler A.M.
        • Lee S.J.
        Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member.
        Nature. 1997; 387: 83-90
        • Shyu K.G.
        • Lu M.J.
        • Wang B.W.
        • Sun H.Y.
        • Chang H.
        Myostatin expression in ventricular myocardium in a rat model of volume-overload heart failure.
        Eur J Clin Invest. 2006; 36: 713-719
        • George I.
        • Bish L.T.
        • Kamalakkannan G.
        • Petrilli C.M.
        • Oz M.C.
        • Naka Y.
        • et al.
        Myostatin activation in patients with advanced heart failure and after mechanical unloading.
        Eur J Heart Fail. 2010; 12: 444-453
        • Gruson D.
        • Ahn S.A.
        • Ketelslegers J.M.
        • Rousseau M.F.
        Increased plasma myostatin in heart failure.
        Eur J Heart Fail. 2011; 13: 734-736
        • Lenk K.
        • Erbs S.
        • Hollriegel R.
        • Beck E.
        • Linke A.
        • Gielen S.
        • et al.
        Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure.
        Eur J Prev Cardiol. 2011; 19: 404-411
        • Li Z.B.
        • Kollias H.D.
        • Wagner K.R.
        Myostatin directly regulates skeletal muscle fibrosis.
        J Biol Chem. 2008; 283: 19371-19378
        • Li Z.B.
        • Zhang J.
        • Wagner K.R.
        Inhibition of myostatin reverses muscle fibrosis through apoptosis.
        J Cell Sci. 2012; 125: 3957-3965
        • Biesemann N.
        • Mendler L.
        • Kostin S.
        • Wietelmann A.
        • Borchardt T.
        • Braun T.
        Myostatin induces interstitial fibrosis in the heart via TAK1 and p38.
        Cell Tissue Res. 2015; 361: 779-787
        • Ellmers L.J.
        • Scott N.J.
        • Medicherla S.
        • Pilbrow A.P.
        • Bridgman P.G.
        • Yandle T.G.
        • et al.
        Transforming growth factor-beta blockade down-regulates the renin-angiotensin system and modifies cardiac remodeling after myocardial infarction.
        Endocrinology. 2008; 149: 5828-5834
        • Anderson B.
        Echocardiography - the normal examination and echocardiographic measurements.
        MGA Graphics, Australia2000
        • Takagawa J.
        • Zhang Y.
        • Wong M.L.
        • Sievers R.E.
        • Kapasi N.K.
        • Wang Y.
        • et al.
        Myocardial infarct size measurement in the mouse chronic infarction model: comparison of area- and length-based approaches.
        J Appl Physiol. 2007; 102: 2104-2111
        • Kitamura M.
        • Shimizu M.
        • Kita Y.
        • Yoshio H.
        • Ino H.
        • Misawa K.
        • et al.
        Quantitative evaluation of the rate of myocardial interstitial fibrosis using a personal computer.
        Jpn Circ J. 1997; 61: 781-786
        • Lutgens E.
        • Daemen M.J.
        • de Muinck E.D.
        • Debets J.
        • Leenders P.
        • Smits J.F.
        Chronic myocardial infarction in the mouse: cardiac structural and functional changes.
        Cardiovasc Res. 1999; 41: 586-593
        • Detre S.
        • Saclani Jotti G.
        • Dowsett M.A.
        A “quickscore” method for immunohistochemical semiquantitation: validation for oestrogen receptor in breast carcinomas.
        J Clin Pathol. 1995; 48: 876-878
        • Michael L.H.
        • Ballantyne C.M.
        • Zachariah J.P.
        • Gould K.E.
        • Pocius J.S.
        • Taffet G.E.
        • et al.
        Myocardial infarction and remodeling in mice: effect of reperfusion.
        Am J Physiol. 1999; 277: H660-H668
        • Salto-Tellez M.
        • Yung Lim S.
        • El-Oakley R.M.
        • Tang T.P.
        • ALmsherqi Z.A.
        • Lim S.K.
        Myocardial infarction in the C57BL/6J mouse: a quantifiable and highly reproducible experimental model.
        Cardiovasc Pathol: the official journal of the Society for Cardiovascular Pathology. 2004; 13: 91-97
        • Ahn D.
        • Cheng L.
        • Moon C.
        • Spurgeon H.
        • Lakatta E.G.
        • Talan M.I.
        Induction of myocardial infarcts of a predictable size and location by branch pattern probability-assisted coronary ligation in C57BL/6 mice.
        Am J Physiol Heart Circ Physiol. 2004; 286: H1201-H1207
        • McPherron A.C.
        • Lee S.J.
        Double muscling in cattle due to mutations in the myostatin gene.
        Proceedings of the National Academy of Sciences of the United States of America. 1997; 94: 12457-12461
        • McPherron A.C.
        • Lee S.J.
        Suppression of body fat accumulation in myostatin-deficient mice.
        J Clin Invest. 2002; 109: 595-601
        • Cohn R.D.
        • Liang H.Y.
        • Shetty R.
        • Abraham T.
        • Wagner K.R.
        Myostatin does not regulate cardiac hypertrophy or fibrosis.
        Neuromuscular Disord: NMD. 2007; 17: 290-296
        • Gould K.E.
        • Taffet G.E.
        • Michael L.H.
        • Christie R.M.
        • Konkol D.L.
        • Pocius J.S.
        • et al.
        Heart failure and greater infarct expansion in middle-aged mice: a relevant model for postinfarction failure.
        Am J Physiol Heart Circ Physiol. 2002; 282: H615-H621
        • Rodgers B.D.
        • Interlichia J.P.
        • Garikipati D.K.
        • Mamidi R.
        • Chandra M.
        • Nelson O.L.
        • et al.
        Myostatin represses physiological hypertrophy of the heart and excitation-contraction couping.
        J Physiol. 2009; 587: 4873-4886
        • Camelliti P.
        • Borg T.K.
        • Kohl P.
        Structural and functional characterisation of cardiac fibroblasts.
        Cardiovasc Res. 2005; 65: 40-51
        • Souders C.A.
        • Bowers S.L.
        • Baudino T.A.
        Cardiac fibroblast: the renaissance cell.
        Circ Res. 2009; 105: 1164-1176
        • Zhu J.
        • Li Y.
        • Shen W.
        • Qiao C.
        • Ambrosio F.
        • Lavasani M.
        • et al.
        Relationships between transforming growth factor-beta1, myostatin, and decorin: implications for skeletal muscle fibrosis.
        J Biol Chem. 2007; 282: 25852-25863
        • Artaza J.N.
        • Singh R.
        • Ferrini M.G.
        • Braga M.
        • Tsao J.
        • Gonzalez-Cadavid N.F.
        Myostatin promotes a fibrotic phenotypic switch in multipotent C3H 10T1/2 cells without affecting their differentiation into myofibroblasts.
        J Endocrinol. 2008; 196: 235-249
        • Morissette M.R.
        • Stricker J.C.
        • Rosenberg M.A.
        • Buranasombati C.
        • Levitan E.B.
        • Mittleman M.A.
        • et al.
        Effects of myostatin deletion in aging mice.
        Aging Cell. 2009; 8: 573-583
        • Morissette M.R.
        • Cook S.A.
        • Foo S.
        • McKoy G.
        • Ashida N.
        • Novikov M.
        • et al.
        Myostatin regulates cardiomyocyte growth through modulation of Akt signaling.
        Circ Res. 2006; 99: 15-24
        • Fraccarollo D.
        • Galuppo P.
        • Bauersachs J.
        Novel therapeutic approaches to post-infarction remodelling.
        Cardiovasc Res. 2012; 94: 293-303