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.
Highlights
Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk
Skeletal muscle mass is controlled by additional mechanisms, such as the tumor growth factor-β family member myostatin and adult stem cells that can be activated in response to regenerative demands[5,11]
Our results indicate that the catalysisdependent pathways of this guanosine nucleotide exchange factors (GEFs) directly impact on insulin growth factor-1 (IGF1) and insulin signaling in the skeletal muscle, as well as in the overall metabolic balance of mice
Summary
Skeletal muscle promotes metabolic balance by regulating glucose uptake and the stimulation of multiple interorgan crosstalk. While hypoactive Vav[2] predisposes to, hyperactive Vav[2] protects against high fat diet-induced metabolic imbalance These data unveil a regulatory layer affecting the signaling output of insulin family factors in muscle. The inhibition of FoxO favors the expression of genes involved in cell metabolism, cell survival, and cell cycle progression It silences genes encoding E3 ubiquitin ligases that contribute to the loss of muscle mass. The same metabolic phenotype is observed when the muscle hypertrophy is triggered via inhibition of myostatin[17,18] These signaling pathways can become dysfunctional in the context of hypercaloric feeding, leading to insulin resistance and lipotoxicity in this tissue[5,8]. Rho GTPases are signaling switchers that cycle between an inactive (GDP-bound) and an active (GTP-bound) state in cells
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