Focal adhesion kinase is a load-dependent governor of the slow contractile and oxidative muscle phenotype

• Published in: The Journal of physiology Vol. 587; no. 14; pp. 3703 - 3717
• Main Authors: Durieux, Anne‐Cécile, D’Antona, Giuseppe, Desplanches, Dominique, Freyssenet, Damien, Klossner, Stephan, Bottinelli, Roberto, Flück, Martin
• Format: Journal Article
• Language: English
• Published: Oxford, UK The Physiological Society 15.07.2009; Blackwell Publishing Ltd; Blackwell Science Inc
• Subjects: Adaptation, Physiological - physiology; Animals; Female; Focal Adhesion Protein-Tyrosine Kinases - physiology; Muscle Contraction - physiology; Muscle, Skeletal - physiology; Oxidation-Reduction; Oxygen - metabolism; Rats; Rats, Wistar; Skeletal Muscle and Exercise
• ISSN: 0022-3751; 1469-7793
• DOI: 10.1113/jphysiol.2009.171355

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.