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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 TGF? 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.

SUBMITTER: Frolova EG

PROVIDER: S-EPMC4150858 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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

Frolova Ella G EG Drazba Judith J Krukovets Irene I Kostenko Volodymyr V Blech Lauren L Harry Christy C Vasanji Amit A Drumm Carla C Sul Pavel P Jenniskens Guido J GJ Plow Edward F EF Stenina-Adognravi Olga O

Matrix biology : journal of the International Society for Matrix Biology 20140301

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-ex ...[more]

PMID: 24589453

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Project description:BackgroundCaenorhabditis elegans has been widely used as a model to study muscle structure and function. Its body wall muscle is functionally and structurally similar to vertebrate skeletal muscle with conserved molecular pathways contributing to sarcomere structure, and muscle function. However, a systematic investigation of the relationship between muscle force and sarcomere organization is lacking. Here, we investigate the contribution of various sarcomere proteins and membrane attachment components to muscle structure and function to introduce C. elegans as a model organism to study the genetic basis of muscle strength.MethodsWe employ two recently developed assays that involve exertion of muscle forces to investigate the correlation of muscle function to sarcomere organization. We utilized a microfluidic pillar-based platform called NemaFlex that quantifies the maximum exertable force and a burrowing assay that challenges the animals to move in three dimensions under a chemical stimulus. We selected 20 mutants with known defects in various substructures of sarcomeres and compared the physiological function of muscle proteins required for force generation and transmission. We also characterized the degree of sarcomere disorganization using immunostaining approaches.ResultsWe find that mutants with genetic defects in thin filaments, thick filaments, and M-lines are generally weaker, and our assays are successful in detecting the functional changes in response to each sarcomere location tested. We find that the NemaFlex and burrowing assays are functionally distinct informing on different aspects of muscle physiology. Specifically, the burrowing assay has a larger bandwidth in phenotyping muscle mutants, because it could pick ten additional mutants impaired while exerting normal muscle force in NemaFlex. This enabled us to combine their readouts to develop an integrated muscle function score that was found to correlate with the score for muscle structure disorganization.ConclusionsOur results highlight the suitability of NemaFlex and burrowing assays for evaluating muscle physiology of C. elegans. Using these approaches, we discuss the importance of the studied sarcomere proteins for muscle function and structure. The scoring methodology we have developed enhances the utility of C. elegans as a genetic model to study muscle function.

Project description:PURPOSE:The gracilis tendon (GT) is a commonly used autologous graft in Orthopaedic surgery. The majority of information on knee function and outcomes after hamstring harvest is related to both semitendinosus and GT harvest. Little is known regarding isolated harvest of a GT. It was hypothesized that isolated GT harvest would lead to altered gait patterns (e.g. augmented anterior-posterior translation or rotation in the tibiofemoral joint) and consequently a higher prevalence of cartilage lesions and meniscal tears in knees. METHODS:GT harvesting was performed on patients with chronic acromioclavicular joint instability without previous knee injuries or surgeries. MRI of both knees and thighs were performed. Knee MRI were evaluated using the Whole-Organ Magnetic Resonance Imaging Score (WORMS). Inter- and intraobserver reliabilities, cross-sectional areas of different muscles, fatty infiltration of the gracilis muscle (GM) and GT regeneration were evaluated. The contralateral limb served as reference. The observers were blinded towards the identity of the patients and the operatively treated side. RESULTS:After a mean time of 44 months after surgery testing was performed on 12 patients. No significant side-to-side differences were found using WORMS, although there was a trend towards increased cartilage lesions after GT harvest (median healthy knee 4.8 and GT harvested knee 7.8 p = 0.086). Inter- and intraobserver repeatability was high with 0.899 (95% confidence interval (CI) 0.708-0.960) and 0.988 (95% CI 0.973-0.995), respectively. A significant hypotrophy of the GM with a mean decrease of 25.3%, 18.4% and 16.9% occurred at 25% (p = 0.016), 50% (p = 0.007) and 75% (p = 0.002) of the length of the femur from distal. No compensatory hypertrophy of other thigh muscles or increased fatty infiltration of the GM was found. Tendon regeneration took place in eight out of 12 patients. In case of regeneration, the regenerated tendon inserted in a more proximal place. CONCLUSION:Isolated harvest of the GT for shoulder procedures did not affect knee MRI significantly indicating therefore in general suitable graft utilization for surgeries outside of the knee. GT regenerated in most patients with just a more proximal insertion and a hypotrophy of the muscle belly.

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

Publications

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

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