title: Quantitative changes in focal adhesion kinase and its inhibitor, FRNK, drive load-dependent expression of costamere components.
abstract: Costameres are mechanosensory sites of focal adhesion in the sarcolemma that reinforce the muscle-fiber composite and provide an anchor for myofibrillogenesis. We hypothesized that elevated content of the integrin-associated regulator of costamere turnover in culture, focal adhesion kinase (FAK), drives changes in costamere component content in antigravity muscle in a load-dependent way in correspondence with altered muscle weight. The content of FAK in soleus muscle being phosphorylated at autoregulatory tyrosine 397 (FAK-pY397) was increased after 20 s of stretch. FAK-pY397 content remained elevated after 24 h of stretch-overload due to upregulated FAK content. Overexpression of FAK in soleus muscle fibers by means of gene electrotransfer increased the β1-integrin (+56%) and meta-vinculin (+88%) content. α7-Integrin (P = 0.46) and γ-vinculin (P = 0.18) content was not altered after FAK overexpression. Co-overexpression of the FAK inhibitor FAK-related nonkinase (FRNK) reduced FAK-pY397 content by 33% and increased the percentage of fast-type fibers that arose in connection with hybrid fibers with gene transfer. Transplantation experiments confirmed the association of FRNK expression with slow-to-fast fiber transformation. Seven days of unloading blunted the elevation of FAK-pY397, β1-integrin, and meta-vinculin content with FAK overexpression, and this was reversed by 1 day of reloading. The results highlight that the expression of components for costameric attachment sites of myofibrils is under load- and fiber type-related control via FAK and its inhibitor FRNK.
authors.affiliation: Department of Anatomy, University of Berne, Berne, Switzerland;
authors.forename: Stephan
authors.initials: S
authors.lastname: Klossner
authors.forename: Ruowei
authors.initials: R
authors.lastname: Li
authors.forename: Severin
authors.initials: S
authors.lastname: Ruoss
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Durieux
authors.forename: Martin
authors.initials: M
authors.lastname: Flück
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D002454:Cell Differentiation; D054974:Costameres; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D018656:Muscle Fibers, Fast-Twitch / Q000166:cytology* / Q000378:metabolism*; D018657:Muscle Fibers, Slow-Twitch / Q000166:cytology* / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C113183:FAK-related nonkinase; D011505:Protein-Tyrosine Kinases; D051416:Focal Adhesion Protein-Tyrosine Kinases
keywords: atrophy; focal adhesion; focal adhesion kinase; focal adhesion kinase-related nonkinase; hypertrophy; muscle; vinculin