Vav2 catalysis-dependent pathways contribute to skeletal muscle growth and metabolic homeostasis
Abstract
Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk. We show here that the catalytic activity of Vav2, a Rho GTPase activator, modulates the signaling output of the IGF1- and insulin-stimulated phosphatidylinositol 3-kinase pathway in that tissue. Consistent with this, mice bearing a Vav2 protein with decreased catalytic activity exhibit reduced muscle mass, lack of proper insulin responsiveness and, at much later times, a metabolic syndrome-like condition. Conversely, mice expressing a catalytically hyperactive Vav2 develop muscle hypertrophy and increased insulin responsiveness. Of note, while hypoactive Vav2 predisposes to, hyperactive Vav2 protects against high fat diet-induced metabolic imbalance. These data unveil a regulatory layer affecting the signaling output of insulin family factors in muscle. ; We also thank the input of S. Virtue on our metabolic data. X.R.B. is supported by grants from the Castilla-León Government (CSI252P18, CLC-2017-01), the Spanish Ministry of Science and Innovation (MSI) (RTI2018-096481-B-100), and the Spanish Association against Cancer (GC16173472GARC). X.R.B.'s institution is supported by the Programa de Apoyo a Planes Estratégicos de Investigación de Estructuras de Investigación de Excelencia of the Castilla-León autonomous government (CLC-2017-01). S.R.-F. and L.F.L.-M. contracts have been mostly supported by funding from the MSI (BES-2013-063573) and the Spanish Ministry of Education, Culture and Sports (L.F.L.-M., FPU13/02923), respectively. Subsequently, they both were supported by the CLC-2017-01 grant. Both Spanish and Castilla-León government-associated funding is partially supported by the European Regional Development Fund.
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