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Matrix Biol. 2014 Jul;37:35-48. doi: 10.1016/j.matbio.2014.02.003. Epub 2014 Mar 1.

Control of organization and function of muscle and tendon by thrombospondin-4.

Author information

1
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
2
Imaging Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
3
Department of Neurology, Neuromuscular Section, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
4
Biomedical Imaging and Analysis Core, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States.
5
Department of Biochemistry 194, University Medical Center, NCMLS, Nijmegen, The Netherlands; ModiQuest Research BV, Nijmegen, The Netherlands.
6
Department of Molecular Cardiology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, United States. Electronic address: stenino@ccf.org.

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.

KEYWORDS:

Glycosaminoglycans; Skeletal muscle; Tendon; Thrombospondin-4

PMID:
24589453
PMCID:
PMC4150858
DOI:
10.1016/j.matbio.2014.02.003
[Indexed for MEDLINE]
Free PMC Article

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