Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice

Abstract

Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism. IntroductionMammalian skeletal muscle has evolved to perform a diverse set of functions, including locomotion, breathing, protecting internal organs, and coordinating global energy expenditure. Skeletal muscle is formed and regenerated through a highly regulated process characterized by myoblast differentiation and fusion into multinucleated syncytia. During embryonic development, specification of mesodermal precursor cells into the myogenic lineage is controlled by signals from surrounding tissues and requires upregulation of several factors, including paired-box transcription factor 7 (pax-7) and basic helix-loop-helix transcriptional activators of the myogenic regulatory factor family, MyoD and Myf-5 (1). The proliferating precursor cells/myoblasts withdraw from the cell cycle and initiate muscle-specific gene expression (2, 3). Myoblasts then initially fuse to form nascent myotubes, with relatively few nuclei, through a highly ordered set of cellular events, including recognition, adhesion, alignment, and membrane union. Subsequent recruitment and fusion of additional myoblasts gives rise to multinucleated myotubes that ultimately mature to give rise to skeletal muscle fibers. The fusion process is controlled, in part, by the actions of calcium-sensitive transcription factors of the nuclear factor of activated T cells (NFAT) family (4, 5). During myoblast fusion,

The relationship between hepatic steatosis and skeletal muscle mass index in men with type 2 diabetes

“…Skeletal muscle protein synthesis is resistant to the anabolic action of insulin in patients with sarcopenia [9]. Signal of insulin-like growth factor (IGF)-1, which has an important role on skeletal muscle mass [37,38], is decreased in insulin resistance [39]. On the other hand, the relationship between insulin resistance and NAFLD has also been recognized [40].…”

MECHANISMS IN ENDOCRINOLOGY: Lessons from growth hormone receptor gene-disrupted mice: are there benefits of endocrine defects?

“…To study the GH action on muscle, two independent muscle-specific GHRKO mice were generated using different promoters/enhancers. The first used Mef-2c-73k promoter/enhancer to knock out GHR in muscle (304); the second used muscle creatine kinase (MCK) promoter/enhancer (305,306,307). Mef-2c-73k is expressed in adult muscle and fetal heart and brain, while MCK is expressed in skeletal and cardiac muscle during all stages of development.…”

“…This difference may be used to explain the differences between these two mouse lines. That is, the changes of growth, body compositions and insulin sensitivities were opposite in these two lines (304,305,306,307,308). Importantly, the MCK males increased maximum lifespan along with decreased inflammation (305,307,308) and they were protected from HF diet-induced metabolic deterioration(306).…”

Insulin and IGF-1 receptors regulate FoxO-mediated signaling in muscle proteostasis

“…Studies using human myoblasts and myotubes suggest that muscle expresses higher levels of IGF-1 receptor (IGF1R) relative to insulin receptor (IR) (9), but in vivo studies suggest that both may be involved in maintenance of muscle mass. For example, genetic inactivation of IGF1R in muscle has been reported to cause a mild decrease in muscle fiber size, and deletion of IR in muscle has been suggested to promote age-related muscle atrophy (10,11). We recently showed that combined loss of IR and IGF1R in muscle induces a marked decrease in muscle mass (12), indicating that signaling via IR and/or IGF1R is necessary for normal muscle growth.…”