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heart: local and systemic actions in cardiac failure and muscle wasting. Am J

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Effects of concurrent strength and endurance training on genes related to myostatin signaling pathway and muscle fiber responses

Abstract WFIKKN1 and WFIKKN2 are two closely related multidomain proteins consisting of a WAP (whey acidic protein)-, a follistatin-, an immunoglobulin-, two Kunitz-type protease inhibitor-domains and an NTR domain (netrin domain). Recent experiments have shown that both WFIKKN1 and WFIKKN2 bind myostatin and GDF11 (growth and differentiation factor 11) with high affinity and are potent antagonists of these growth factors. Structure-function studies on WFIKKN proteins have revealed that their interactions with GDF8 and GDF11 are mediated primarily by the follistatin and NTR domains. Structure and evolution of WFIKKN proteins Using sensitive homology-search and gene-finding programmes, we have identified two closely related human genes, WFIKKN1 and WFIKKN2 (originally designated as WFIKKN and WFIKKNRP) on chromosomes 16 and 17 respectively Searches of public databases have identified full-length orthologues of WFIKKN proteins from urochordates (Ciona intestinalis), all groups of vertebrates (lamprey, bony fishes, frog, chicken and mammals), but not from non-chordate animals, suggesting that the common ancestor of WFIKKN proteins was formed in the chordate lineage The WFIKKN protein of C. intestinalis, however, differs from vertebrate proteins in that it lacks an immunoglobulin domain. Phylogenetic analyses of domains shared by WFIKKN-related proteins of urochordates and vertebrates have revealed that the Ciona protein is basal to WFIKKN1 and WFIKKN2 branches, indicating that the gene duplication of the ancestral WFIKKN gene occurred in vertebrata after their divergence from urochordata, their closest invertebrate relatives The genomes of chicken and mammals were found to contain single WFIKKN1 and WFIKKN2 genes, but in the case of completely sequenced fish genomes (Fugu rubripes, Tetraodon nigroviridens and Danio rerio), there was evidence Key words: growth and differentiation factor 11 (GDF11), growth factor antagonist, myostatin, protease inhibitor, transforming growth factor β (TGFβ), WFIKKN. Abbreviations used: ACRIIB, activin receptor IIB; BMP, bone morphogenetic protein; BPTI, bovine pancreatic trypsin inhibitor; GDF, growth and differentiation factor; NTR domain, netrin domain; SPR, surface plasmon resonance; TGFβ, transforming growth factor β; WAP, whey acidic protein. for a single WFIKKN1-and two WFIKKN2-related genes Expression of WFIKKN proteins Studies on the tissue-expression pattern of the two human WFIKKN genes have revealed pronounced differences. Whereas the WFIKKN1 gene is expressed primarily in pancreas, liver, thymus, kidney and lung, significant expression of the WFIKKN2 gene is observed in ovary, testis and brain. In human fetal tissues, the expression of WFIKKN1 was highest in lung, skeletal muscle and liver, whereas WFIKKN2 expression was found in brain, skeletal muscle, kidney and thymus Molecular interactions of WFIKKN proteins WFIKKN1 and WFIKKN2 proteins inhibit the activity of trypsin WFIKKN proteins contain several domain types that have been implicated in inhibition of various types of proteases: the WAP-and Kunitz-type protease inhibitor modules frequently function as serine protease inhibitors To test this hypothesis, we have produced the recombinant full-length WFIKKN1 and WFIKKN2 proteins, some of their domains and domain combinations and studied their effect on the proteolytic activity of various proteases. Fulllength WFIKKN proteins inhibited the proteolytic activity of bovine trypsin but had no effect on the peptidolytic activity of bovine elastase, chymotrypsin, tissue-type plasminogen activator, urokinase-type plasminogen activator, furin and C

Devant le jury composé de:

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à la Faculté des études supérieures de l'Université Laval dans le cadre du programme de doctorat en biologie moléculaire et cellulaire pour l'obtention du grade de Philosophiae Doctor (PhD)

thesis of JILLIAN PATRICE