title: Focal adhesion kinase is a load-dependent governor of the slow contractile and oxidative muscle phenotype.
abstract: Striated muscle exhibits a pronounced structural-functional plasticity in response to chronic alterations in loading. We assessed the implication of focal adhesion kinase (FAK) signalling in mechano-regulated differentiation of slow-oxidative muscle. Load-dependent consequences of FAK signal modulation were identified using a multi-level approach after electrotransfer of rat soleus muscle with FAK-expression plasmid vs. empty plasmid-transfected contralateral controls. Muscle fibre-targeted over-expression of FAK in anti-gravitational muscle for 9 days up-regulated transcript levels of gene ontologies underpinning mitochondrial metabolism and contraction in the transfected belly portion. Concomitantly, mRNA expression of the major fast-type myosin heavy chain (MHC) isoform, MHC2A, was reduced. The promotion of the slow-oxidative expression programme by FAK was abolished after co-expression of the FAK inhibitor FAK-related non-kinase (FRNK). Elevated protein content of MHC1 (+9%) and proteins of mitochondrial respiration (+165-610%) with FAK overexpression demonstrated the translation of transcript differentiation in targeted muscle fibres towards a slow-oxidative muscle phenotype. Coincidentally MHC2A protein was reduced by 50% due to protection of muscle from de-differentiation with electrotransfer. Fibre cross section in FAK-transfected muscle was elevated by 6%. The FAK-modulated muscle transcriptome was load-dependent and regulated in correspondence to tyrosine 397 phosphorylation of FAK. In the context of overload, the FAK-induced gene expression became manifest at the level of contraction by a slow transformation and the re-establishment of normal muscle force from the lowered levels with transfection. These results highlight the analytic power of a systematic somatic transgene approach by mapping a role of FAK in the dominant mechano-regulation of muscular motor performance via control of gene expression.
authors.affiliation: Institute for Anatomy, University of Berne, Berne, Switzerland.
authors.forename: Anne-Cécile
authors.initials: AC
authors.lastname: Durieux
authors.forename: Giuseppe
authors.initials: G
authors.lastname: D'Antona
authors.forename: Dominique
authors.initials: D
authors.lastname: Desplanches
authors.forename: Damien
authors.initials: D
authors.lastname: Freyssenet
authors.forename: Stephan
authors.initials: S
authors.lastname: Klossner
authors.forename: Roberto
authors.initials: R
authors.lastname: Bottinelli
authors.forename: Martin
authors.initials: M
authors.lastname: Flück
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D005260:Female; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000502:physiology*; D009119:Muscle Contraction / Q000502:physiology*; D018482:Muscle, Skeletal / Q000502:physiology*; D010084:Oxidation-Reduction; D010100:Oxygen / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
chemical_list: D051416:Focal Adhesion Protein-Tyrosine Kinases; D010100:Oxygen