the role of skeletal muscle akt signaling in the regulation of … · 2020. 11. 16. · akt...

The Role Of Skeletal Muscle Akt Signaling In The Regulation Of Muscle Growth And Function

Skeletal muscle accounts for more than 40% of the body mass, providing means forlocomotion at the expense of cellular energy. They rely on distinct metabolic pathways tomeet this energic demand. Insulin and insulin-like-growth factor 1 signaling control skeletalmuscle growth and function and defects in these underlie a host of skeletal muscle diseases;however, the molecular mechanisms mediating these effects remain ill-defined. Tounderstand the signaling mechanisms controlling insulin and IGF-1 regulation of skeletalmuscle physiology, we generated mice lacking Akt, an essential downstream signalingmolecule with skeletal muscle specific deletion of Akt2 (M-Akt2KO), the predominant Aktisoform in skeletal muscle, and Akt1 and Akt2 (M-AktDKO), to delete both the Akt isoforms inmuscles. Surprisingly, despite a reduction of ~90% of total Akt following Akt2 deletion alone,M-Akt2KO had normal muscle mass and no apparent phenotype. In contrast, M-AktDKOmice have significant reduction in muscle mass resulting in lower absolute force generationand impaired in vivo performance accompanied by the loss of oxidative fibers.Mechanistically, the activation of mTORC1 and inhibition of FOXO1 are both required andsufficient for the regulation of muscle mass and exercise performance downstream of Akt.

Abstract

Natasha Jaiswal1, Matthew Gavin1, Emanuele Loro2,3, Timothy S. Luongo1, Fuentes N, Joseph Baur1,2, Tejvir S. Khurana2,3, Paul M. Titchenell1,21Institute for Diabetes, Obesity, and Metabolism, 2Department of Physiology, 3Penn Muscle Institute,

Perelman School of Medicine at the University of Pennsylvania

Role of Insulin/IGF-1 signaling in skeletal muscle physiology

A B

Figure 1. Insulin signaling in skeletal muscle. A) Insulin signals through muscle IR and IGF1-R toactivate skeletal muscle Akt which stimulates muscle growth and function B) Predicted effects of loss ofAkt on muscle growth and whole body performance

Loss of both Akt isoforms in skeletal Muscle reduces muscle mass

Figure 3. M-AktDKO miceexhibit reduced body weightand muscle mass. A) Bodyweight of control and Knockoutmice B) Individual weights ofeach muscle fiber of differentmice group (males) and C) theRepresentative image of musclesfrom Control and M-AktDKO miceD) Western blot of Quadricepsmuscle following insulin injection.*M-Akt1KO did not show anydefect in muscle mass (data notshown) **p