Increased Insulin Action, Glucose Metabolism and Muscle Function in Supervillin-Knockout and Supervillin-Mutant Mice.

Abstract

We here describe mouse models with complementary homozygous Svil mutations. In skeletal muscle, Svil-Mut mice express the Svil-encoded N-terminus fused to the βgal-neo gene-trap tag and lack the highly conserved archvillin C-terminus; Svil-KO mice lack expression of all known Svil-encoded proteins; and Svil-LoxP mice contain loxP sites for tissue-specific disruption of protein expression. Older Svil-KO male mice showed decreased levels of markers for type 1, 2a, and 2b muscle fibers. Male mice showed elevated P-ERK/ERK signaling during lengthening contractions, consistent with low-level muscle damage such as that in myofibrillar myopathy-10 (MFM10) in humans lacking SVIL proteins. Female mice lacking full-length Svil-encoded proteins, including supervillin and archvillin, exhibited reduced body weights and reduced fat mass. Females in both strains exhibited improved glucose tolerance and lower insulin levels following intraperitoneal glucose injections. Hyperinsulinemic-euglycemic clamp experiments showed increased insulin sensitivity in both strains and increased glucose metabolism in adipose tissues in female Svil-Mut mice. The GLUT4 glucose transporter was increased in skeletal muscle in breeder-aged female Svil-KO and Svil-Mut mice. RNA-Seq revealed transcriptional differences in adult male homeostatic muscles that supported roles in muscle differentiation, ERK signaling, and lipid metabolism. A yeast two-hybrid screen identified new Svil candidate interactors, including CH1 domains of muscle Z-line proteins, a potential dimerization site, and Rho GTPase-activating protein (ARHGAP21), a negative regulator of glucose-stimulated insulin secretion in pancreatic beta cells. We suggest that the Svil-Mut, Svil-KO, and Svil-LoxP strains described here will be useful models for understanding signaling within and between tissues regulating glucose metabolism.