Ablation of Grb10 Specifically in Muscle Impacts Muscle Size and Glucose Metabolism in Mice

Lowenna J. Holt, Amanda E. Brandon, Lewin Small, Eurwin Suryana, Elaine Preston, Donna Wilks, Nancy Mokbel, Chantal A. Coles, Jason D. White, Nigel Turner, Roger J. Daly, Gregory J. Cooney

Research output: Contribution to journalArticleResearchpeer-review

4 Citations (Scopus)

Abstract

Grb10 is an adaptor-type signaling protein most highly expressed in tissues involved in insulin action and glucose metabolism, such as muscle, pancreas, and adipose. Germline deletion of Grb10 in mice creates a phenotype with larger muscles and improved glucose homeostasis. However, it has not been determined whether Grb10 ablation specifically in muscle is sufficient to induce hypermuscularity or affect whole body glucose metabolism. In this study we generated muscle-specific Grb10-deficient mice (Grb10-mKO) by crossing Grb10 flox/flox mice with mice expressing Cre recombinase under control of the human α-skeletal actin promoter. One-year-old Grb10-mKO mice had enlarged muscles, with greater cross-sectional area of fibers compared with wild-type (WT) mice. This degree of hypermuscularity did not affect whole body glucose homeostasis under basal conditions. However, hyperinsulinemic/euglycemic clamp studies revealed that Grb10-mKO mice had greater glucose uptake into muscles compared with WT mice. Insulin signaling was increased at the level of phospho-Akt in muscle of Grb10-mKO mice compared with WT mice, consistent with a role of Grb10 as a modulator of proximal insulin receptor signaling. We conclude that ablation of Grb10 in muscle is sufficient to affect muscle size and metabolism, supporting an important role for this protein in growth and metabolic pathways.

Original languageEnglish
Pages (from-to)1339-1351
Number of pages13
JournalEndocrinology
Volume159
Issue number3
DOIs
Publication statusPublished - 1 Mar 2018

Cite this

Holt, L. J., Brandon, A. E., Small, L., Suryana, E., Preston, E., Wilks, D., ... Cooney, G. J. (2018). Ablation of Grb10 Specifically in Muscle Impacts Muscle Size and Glucose Metabolism in Mice. Endocrinology, 159(3), 1339-1351. https://doi.org/10.1210/en.2017-00851
Holt, Lowenna J. ; Brandon, Amanda E. ; Small, Lewin ; Suryana, Eurwin ; Preston, Elaine ; Wilks, Donna ; Mokbel, Nancy ; Coles, Chantal A. ; White, Jason D. ; Turner, Nigel ; Daly, Roger J. ; Cooney, Gregory J. / Ablation of Grb10 Specifically in Muscle Impacts Muscle Size and Glucose Metabolism in Mice. In: Endocrinology. 2018 ; Vol. 159, No. 3. pp. 1339-1351.
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abstract = "Grb10 is an adaptor-type signaling protein most highly expressed in tissues involved in insulin action and glucose metabolism, such as muscle, pancreas, and adipose. Germline deletion of Grb10 in mice creates a phenotype with larger muscles and improved glucose homeostasis. However, it has not been determined whether Grb10 ablation specifically in muscle is sufficient to induce hypermuscularity or affect whole body glucose metabolism. In this study we generated muscle-specific Grb10-deficient mice (Grb10-mKO) by crossing Grb10 flox/flox mice with mice expressing Cre recombinase under control of the human α-skeletal actin promoter. One-year-old Grb10-mKO mice had enlarged muscles, with greater cross-sectional area of fibers compared with wild-type (WT) mice. This degree of hypermuscularity did not affect whole body glucose homeostasis under basal conditions. However, hyperinsulinemic/euglycemic clamp studies revealed that Grb10-mKO mice had greater glucose uptake into muscles compared with WT mice. Insulin signaling was increased at the level of phospho-Akt in muscle of Grb10-mKO mice compared with WT mice, consistent with a role of Grb10 as a modulator of proximal insulin receptor signaling. We conclude that ablation of Grb10 in muscle is sufficient to affect muscle size and metabolism, supporting an important role for this protein in growth and metabolic pathways.",
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Holt, LJ, Brandon, AE, Small, L, Suryana, E, Preston, E, Wilks, D, Mokbel, N, Coles, CA, White, JD, Turner, N, Daly, RJ & Cooney, GJ 2018, 'Ablation of Grb10 Specifically in Muscle Impacts Muscle Size and Glucose Metabolism in Mice', Endocrinology, vol. 159, no. 3, pp. 1339-1351. https://doi.org/10.1210/en.2017-00851

Ablation of Grb10 Specifically in Muscle Impacts Muscle Size and Glucose Metabolism in Mice. / Holt, Lowenna J.; Brandon, Amanda E.; Small, Lewin; Suryana, Eurwin; Preston, Elaine; Wilks, Donna; Mokbel, Nancy; Coles, Chantal A.; White, Jason D.; Turner, Nigel; Daly, Roger J.; Cooney, Gregory J.

In: Endocrinology, Vol. 159, No. 3, 01.03.2018, p. 1339-1351.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Holt, Lowenna J.

AU - Brandon, Amanda E.

AU - Small, Lewin

AU - Suryana, Eurwin

AU - Preston, Elaine

AU - Wilks, Donna

AU - Mokbel, Nancy

AU - Coles, Chantal A.

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AU - Turner, Nigel

AU - Daly, Roger J.

AU - Cooney, Gregory J.

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Holt LJ, Brandon AE, Small L, Suryana E, Preston E, Wilks D et al. Ablation of Grb10 Specifically in Muscle Impacts Muscle Size and Glucose Metabolism in Mice. Endocrinology. 2018 Mar 1;159(3):1339-1351. https://doi.org/10.1210/en.2017-00851