title: Control of organization and function of muscle and tendon by thrombospondin-4.
abstract: Thrombospondins (TSPs) are multifunctional proteins that are deposited in the extracellular matrix where they directly affect the function of vascular and other cell types. TSP-4, one of the 5 TSP family members, is expressed abundantly in tendon and muscle. We have examined the effect of TSP-4 deficiency on tendon collagen and skeletal muscle morphology and function. In Thbs4(-/-) mice, tendon collagen fibrils are significantly larger than in wild-type mice, and there is no compensatory over-expression of TSP-3 and TSP-5, the two TSPs most highly homologous to TSP-4, in the deficient mice. TSP-4 is expressed in skeletal muscle, and higher levels of TSP-4 protein are associated with the microvasculature of red skeletal muscle with high oxidative metabolism. Lack of TSP-4 in medial soleus, red skeletal muscle with predominant oxidative metabolism, is associated with decreased levels of several specific glycosaminoglycan modifications, decreased expression of a TGFβ receptor beta-glycan, decreased activity of lipoprotein lipase, which associates with vascular cell surfaces by binding to glycosaminoglycans, and decreased uptake of VLDL. The soleus muscle is smaller and hind- and fore-limb grip strength is reduced in Thbs4(-/-) mice compared to wild-type mice. These observations suggest that TSP-4 regulates the composition of the ECM at major sites of its deposition, tendon and muscle, and the absence of TSP-4 alters the organization, composition and physiological functions of these tissues.
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Ella G
authors.initials: EG
authors.lastname: Frolova
authors.affiliation: Imaging Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Judith
authors.initials: J
authors.lastname: Drazba
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Irene
authors.initials: I
authors.lastname: Krukovets
authors.affiliation: Department of Neurology, Neuromuscular Section, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Volodymyr
authors.initials: V
authors.lastname: Kostenko
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Lauren
authors.initials: L
authors.lastname: Blech
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Christy
authors.initials: C
authors.lastname: Harry
authors.affiliation: Biomedical Imaging and Analysis Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Amit
authors.initials: A
authors.lastname: Vasanji
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Carla
authors.initials: C
authors.lastname: Drumm
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Pavel
authors.initials: P
authors.lastname: Sul
authors.affiliation: Department of Biochemistry 194, University Medical Center, NCMLS, Nijmegen, The Netherlands; ModiQuest Research BV, Nijmegen, The Netherlands.
authors.forename: Guido J
authors.initials: GJ
authors.lastname: Jenniskens
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Plow
authors.affiliation: Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States. Electronic address: stenino@ccf.org.
authors.forename: Olga
authors.initials: O
authors.lastname: Stenina-Adognravi
mesh_terms: D000818:Animals; D015153:Blotting, Western; D003094:Collagen / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D042783:Endothelial Cells / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D006025:Glycosaminoglycans / Q000378:metabolism; D006497:Heparan Sulfate / Q000378:metabolism; D007150:Immunohistochemistry; D008079:Lipoproteins, VLDL / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D053580:Muscle Strength / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000502:physiology*; D013710:Tendons / Q000378:metabolism / Q000502:physiology*; D019699:Thrombospondins / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*
chemical_list: D003094:Collagen; D017931:DNA Primers; D016326:Extracellular Matrix Proteins; D006025:Glycosaminoglycans; D006497:Heparan Sulfate; D008079:Lipoproteins, VLDL; D019699:Thrombospondins; C101864:thrombospondin 4
keywords: Glycosaminoglycans; Skeletal muscle; Tendon; Thrombospondin-4