PHYSIOLOGY AND ENDOCRINOLOGY SYMPOSIUM: Roles for insulin-supported skeletal muscle growth1,2

Abstract

Basic principles governing skeletal muscle growth and development, from a cellular point of view, have been realized for several decades. Skeletal muscle is marked by the capacity for rapid hypertrophy and increases in protein content. Ultimately, skeletal muscle growth is controlled by 2 basic means: 1) myonuclear accumulation stemming from satellite cell (myoblast) proliferation and 2) the balance of protein synthesis and degradation. Each process underlies the rapid changes in lean tissue accretion evident during fetal and neonatal growth and is particularly sensitive to nutritional manipulation. Although multiple signals converge to alter skeletal muscle mass, postprandial changes in the anabolic hormone insulin link feed intake with enhanced rates of protein synthesis in the neonate. Indeed, a consequence of insulin-deficient states such as malnutrition is reduced myoblast activity and a net loss of body protein. A well-characterized mechanism mediating the anabolic effect of insulin involves the phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) signaling pathway. Activation of mTOR leads to translation initiation control via the phosphorylation of downstream targets. Modulation of this pathway by insulin, as well as by other hormones and nutrients, accounts for enhanced protein synthesis leading to efficient lean tissue accretion and rapid skeletal muscle gain in the growing animal. Dysfunctional insulin activity during fetal and neonatal stages likely alters growth through cellular and protein synthetic capacities.

SCO‐792, an enteropeptidase inhibitor, improves disease status of diabetes and obesity in mice

“…Thus, the modulation of amino acid absorption by enteropeptidase inhibition may be an early event that eventually results in improved insulin sensitivity in the diabetic condition. Considering the pivotal role of insulin signaling in the maintenance of muscle mass, increased insulin sensitivity in muscle may explain why SCO‐792‐treated mice show unaltered lean mass despite body weight loss. Interestingly, glucose uptake in fat was decreased in the hyperinsulinaemic‐euglycaemic condition.…”

“…27 Thus, the modulation of amino acid absorption by enteropeptidase inhibition may be an early event that eventually results in improved insulin sensitivity in the diabetic condition. Considering the pivotal role of insulin signaling in the maintenance of muscle mass, 28 weight, which increased abnormally in ob/ob mice, decreased upon treatment with SCO-792. As it is widely accepted that liver lipotoxicity induces nonalcoholic steatohepatitis, 30 SCO-792-treatment may also offer benefits for this condition.…”

Downregulated Translation Initiation Signaling Predisposes Low-Birth-Weight Neonatal Pigs to Slower Rates of Muscle Protein Synthesis

“…Postnatal muscle growth is driven by two basic mechanisms (Rhoads et al, 2016). The first is through satellite cell-mediated myonuclear incorporation, which takes place via proliferation and fusion of satellite cells (Wozniak et al, 2005).…”

Crucial role of androgen receptor in resistance and endurance trainings-induced muscle hypertrophy through IGF-1/IGF-1R- PI3K/Akt- mTOR pathway

“…IGF-1/IGF-1R mainly exert their functions in facilitating proliferation of muscle cells and muscle hypertrophy on untrained or un-stretched state through stimulating PI3K/Akt and thereby activating mTOR [16,32] , and antagonist of PI3K could significantly inhibit the activation of mTOR in C2C12 cells [33] . For trained state, our previous work in vitro demonstrated the vital effects of IGF-1/IGF-1R on mechanical stretch-induced pro-proliferation of myoblasts by activating PI3K/Akt-mTOR using exogenous IGF-1, IGF-1R neutralizing antibody, and inhibitors of PI3K/Akt [23,24] .…”