Download PDF
Int J Sports Med 2013; 34(09): 789-794
DOI: 10.1055/s-0032-1333284
Physiology & Biochemistry
© Georg Thieme Verlag KG Stuttgart · New York

The Fibrotic Role of Phosphatidylinositol-3-kinase/Akt Pathway in Injured Skeletal Muscle after Acute Contusion

H.-Y. Li
1   Department of Sports Medicine, Huashan Hospital, Sports Medicine Center of Fudan University, Shanghai, China
,
Q.-G. Zhang
2   Department of orthopaedics, Taizhou Hospital, Taizhou, Zhejiang, China
,
J.-W. Chen
1   Department of Sports Medicine, Huashan Hospital, Sports Medicine Center of Fudan University, Shanghai, China
,
S.-Q. Chen
1   Department of Sports Medicine, Huashan Hospital, Sports Medicine Center of Fudan University, Shanghai, China
,
S.-Y. Chen
1   Department of Sports Medicine, Huashan Hospital, Sports Medicine Center of Fudan University, Shanghai, China
› Author Affiliations
Further Information

Publication History



accepted after revision 18 December 2012

Publication Date:
26 February 2013 (online)

Also available at
    Permissions and Reprints

Abstract

Transforming growth factor β (TGF-β) is a multifunctional cytokine with fibrogenic properties. Previous studies demonstrated that Phosphatidylinositol 3-Kinase (PI3K)/Akt/ mammalian target of Ramycin (mTOR), a non-Smad TGF-β pathway, plays an important role in the fibrotic pathogenesis of different organs such as the lung, kidney, skin and liver. However, the role of PI3k-Akt pathway in fibrosis in injured skeletal muscle is still unclear. In this study, we determined the fibrotic role of PI3K-Akt pathway in injured skeletal muscle. We established a mouse model for acute muscle contusion. Western blotting analysis showed that TGF-β, phosphorylated Akt and phosphorylated mTOR were increased in muscles after acute contusion, which indicated that the PI3K-Akt- mTOR pathway was activated in skeletal muscle after acute contusion. The pathway was inhibited by a PI3K inhibitor, LY294002. Moreover, the expression of fibrosis markers vimentin, α SMA and collagen I and the area of scar decreased in injured skeletal muscle after PI3K pathway was blocked. The muscle function improved in terms of both fast-twitch and tetanic strength after PI3K/Akt pathway was inhibited in injured skeletal muscle. In conclusion, activation of PI3K-Akt-mTOR pathway might promote collagen production and scar formation in the acute contused skeletal muscle. Blocking of PI3K-Akt-mTOR pathway could improve the function of injured skeletal muscle.

Key words

Fibrosis - muscle injuries - phosphatidylinositol-3-kinase - akt - mammalian target of ­Ramycin
 

  • References

  • 1 Border WA, Noble NA. Transforming growth factor in tissue fibrosis. N Engl J Med 1994; 331: 1286-1292
    CrossrefPubMedGoogle Scholar
  • 2 Bouzeghrane F, Mercure C, Reudelhuber TL, Thibault G. Alpha8beta1 integrin is upregulated in myofibroblasts of fibrotic and scarring myocardium. J Mol Cell Cardiol 2004; 36: 343-353
    CrossrefPubMedGoogle Scholar
  • 3 Cantley LC. The phosphoinositide 3-kinase pathway. Science 2002; 296: 1655-1657
    CrossrefPubMedGoogle Scholar
  • 4 Conte E, Fruciano M, Fagone E, Gili E, Caraci F, Iemmolo M, Crimi N, Vancheri C. Inhibition of PI3K prevents the proliferation and differentiation of human lung fibroblasts into myofibroblasts: the role of class I P110 isoforms. PLoS One 2011; 6: e24663
    CrossrefPubMedGoogle Scholar
  • 5 Foster W, Li Y, Usas A, Somogyi G, Huard J. Gamma interferon as an antifibrosis agent in skeletal muscle. J Orthop Res 2003; 21: 798-804
    CrossrefPubMedGoogle Scholar
  • 6 Garrett Jr WE. Muscle strain injuries. Am J Sports Med 1996; 24: S2-S8
    CrossrefPubMedGoogle Scholar
  • 7 Gharbi SI, Zvelebil MJ, Shuttleworth SJ, Hancox T, Saghir N, Timms JF, Waterfield MD. Exploring the specificity of the PI3K family inhibitor LY294002. Biochem J 2007; 404: 15-21
    CrossrefPubMedGoogle Scholar
  • 8 Guo L, Chen L, Bi S, Chai L, Wang Z, Cao C, Tao L, Li S. PTEN inhibits proliferation and functions of hypertrophic scar fibroblasts. Mol Cell Biochem 2012; 361: 161-168
    CrossrefPubMedGoogle Scholar
  • 9 Harriss DJ, Atkinson G. Update – ethical standards in sport and exercise science research. Int J Sports Med 2011; 32: 819-821
    Article in Thieme ConnectPubMedGoogle Scholar
  • 10 Järvinen TA, Järvinen TL, Kääriäinen M, Kalimo H, Järvinen M. Muscle injuries: biology and treatment. Am J Sports Med 2005; 33: 745-764
    CrossrefPubMedGoogle Scholar
  • 11 Kääriäinen M, Kääriäinen J, Järvinen TL, Nissinen L, Heino J, Järvinen M, Kalimo H. Integrin and dystrophin associated protein complexes during regeneration of shearing-type muscle injury. Neuromuscul Disord 2000; 10: 121-132
    CrossrefPubMedGoogle Scholar
  • 12 Kasemkijwattana C, Menetrey J, Somogyl G, Moreland MS, Fu FH, Buranapanitkit B, Watkins SC, Huard J. Development of approaches to improve the healing following muscle contusion. Cell Transplant 1998; 7: 585-598
    CrossrefPubMedGoogle Scholar
  • 13 Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J 2004; 18: 816-827
    CrossrefPubMedGoogle Scholar
  • 14 Li Y, Foster W, Deasy BM, Chan Y, Prisk V, Tang Y, Cummins J, Huard J. Transforming growth factor-beta 1 induces the differentiation of myogenic cells into fibrotic cells in injured skeletal muscle. Am J Pathol 2004; 164: 1007-1019
    CrossrefPubMedGoogle Scholar
  • 15 Li Y, Huard J. Differentiation of muscle-derived cells into myofibroblasts in injured skeletal muscle. Am J Pathol 2002; 161: 895-907
    CrossrefPubMedGoogle Scholar
  • 16 Lu Y, Azad N, Wang L, Iyer AK, Castranova V, Jiang BH, Rojanasakul Y. Phosphatidylinositol-3-kinase/akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am J Respir Cell Mol Biol 2010; 42: 432-441
    CrossrefPubMedGoogle Scholar
  • 17 Menetrey J, Kasemkijwattana C, Day CS, Bosch P, Vogt M, Fu FH, Moreland MS, Huard J. Growth factors improve muscle healing in vivo. J Bone Joint Surg Br 2000; 82: 131-137
    CrossrefPubMedGoogle Scholar
  • 18 Moyer AL, Wagner KR. Regeneration versus fibrosis in skeletal muscle. Curr Opin Rheumatol 2011; 23: 568-573
    CrossrefPubMedGoogle Scholar
  • 19 Mu Y, Gudey SK, Landström M. Non-Smad signaling pathways. Cell Tissue Res 2012; 347: 11-20
    CrossrefPubMedGoogle Scholar
  • 20 Nakerakanti S, Trojanowska M. The role of TGF-β receptors in fibrosis. Open Rheumatol J 2012; 6: 156-162
    CrossrefPubMedGoogle Scholar
  • 21 Nozaki M, Li Y, Zhu J, Ambrosio F, Uehara K, Fu FH, Huard J. Improved muscle healing after contusion injury by the inhibitory effect of suramin on myostatin, a negative regulator of muscle growth. Am J Sports Med 2008; 36: 2354-2362
    CrossrefPubMedGoogle Scholar
  • 22 Nozaki M, Ota S, Terada S, Li Y, Uehara K, Gharaibeh B, Fu FH, Huard J. Timing of the administration of suramin treatment after muscle injury. Muscle Nerve 2012; 46: 70-79
    CrossrefPubMedGoogle Scholar
  • 23 Parapuram SK, Shi-wen X, Elliott C, Welch ID, Jones H, Baron M, Denton CP, Abraham DJ, Leask A. Loss of PTEN expression by dermal fibroblasts causes skin fibrosis. J Invest Dermatol 2011; 131: 1996-2003
    CrossrefPubMedGoogle Scholar
  • 24 Sato K, Li Y, Foster W, Fukushima K, Badlani N, Adachi N, Usas A, Fu FH, Huard J. Improvement of muscle healing through enhancement of muscle regeneration and prevention of fibrosis. Muscle Nerve 2003; 28: 365-372
    CrossrefPubMedGoogle Scholar
  • 25 Smith CA, Stauber F, Waters C, Alway SE, Stauber WT. Transforming growth factor-beta following skeletal muscle strain injury in rats. J Appl Physiol 2007; 102: 755-761
    PubMedGoogle Scholar
  • 26 Son G, Hines IN, Lindquist J, Schrum LW, Rippe RA. Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis. Hepatology 2009; 50: 1512-1523
    CrossrefPubMedGoogle Scholar
  • 27 Turgeman T, Hagai Y, Huebner K, Jassal DS, Anderson JE, Genin O, Nagler A, Halevy O, Pines M. Prevention of muscle fibrosis and improvement in muscle performance in the mdx mouse byhalofuginone. Neuro­muscul Disord 2008; 18: 857-868
    PubMedGoogle Scholar
  • 28 Ulloa L, Doody J, Massagué J. Inhibition of transforming growth factor-beta/SMAD signalling by the interferon-gamma/STAT pathway. Nature 1999; 397: 710-713
    CrossrefPubMedGoogle Scholar
  • 29 Vaittinen S, Hurme T, Rantanen J, Kalimo H. Transected myofibres may remain permanently divided in two parts. Neuromuscul Disord 2002; 12: 584-587
    CrossrefPubMedGoogle Scholar
  • 30 White ES, Atrasz RG, Hu B, Phan SH, Stambolic V, Mak TW, Hogaboam CM, Flaherty KR, Martinez FJ, Kontos CD, Toews GB. Negative regulation of myofibroblast differentiation by PTEN (phosphatase and tensin homolog deleted on chromosome 10). Am J Respir Crit Care Med 2006; 173: 112-121
    CrossrefPubMedGoogle Scholar
  • 31 Wilkes MC, Leof EB. Transforming growth factor beta activation of c-Abl is independent of receptor internalization and regulated by phosphatidylinositol 3-kinase and PAK2 in mesenchymal cultures. J Biol Chem 2006; 281: 27846-27854
    CrossrefPubMedGoogle Scholar
  • 32 Winbanks CE, Grimwood L, Gasser A, Darby IA, Hewitson TD, Becker GJ. Role of the phosphatidylinositol 3-kinase and mTOR pathways in the regulation of renal fibroblast function and differentiation. Int J Biochem Cell Biol 2007; 39: 206-219
    CrossrefPubMedGoogle Scholar