Muscle IGF-1-Induced Skeletal Muscle Hypertrophy Evokes Higher Insulin Sensitivity and Carbohydrate Use as Preferential Energy Substrate

Abstract

We characterized the metabolic profile of transgenic mice exhibiting enhanced muscle mass driven by increased mIGF-1 expression (MLC/mIGF-1). As expected, 6-month-old MLC/mIGF-1 mice were heavier than age-matched wild type (WT) mice (37.4 ± 0.3 versus 31.8 ± 0.6 g, resp.). MLC/mIGF-1 mice had higher respiratory quotient when compared to WT (0.9 ± 0.03 versus 0.74 ± 0.02, resp.) suggesting a preference for carbohydrate as the major fuel source. MLC/mIGF-1 mice had a higher rate of glucose disposal when compared to WT (3.25 ± 0.14 versus 2.39 ± 0.03%/min, resp.). The higher disposal rate correlated to ∼2-fold higher GLUT4 content in the extensor digitorum longus (EDL) muscle. Analysis of mRNA content for the glycolysis-related gene PFK-1 showed ∼3-fold upregulation in MLC/mIGF-1 animals. We also found a 50% downregulation of PGC1α mRNA levels in MLC/mIGF-1 mouse EDL muscle, suggesting less abundant mitochondria in this tissue. We found no difference in the expression of PPARα and PPARβ/δ, suggesting no modulation of key elements in oxidative metabolism. These data together suggest a shift in metabolism towards higher carbohydrate utilization, and that could explain the increased insulin sensitivity of hypertrophied skeletal muscle in MLC/mIGF-1 mice.

SIRT1 may play a crucial role in overload‐induced hypertrophy of skeletal muscle

“…Indeed, it has been shown that glucose restriction results in depletion of NAD + and Nampt levels and decreased activity of SIRT1, which was associated with impaired myogenesis (Fulco et al 2008). The increased need for energy to cover anabolic processes is supported by the finding that GLUT4 content was increased in our hypertrophy model, in accordance with findings of earlier studies (Kruger et al 2013;Christoffolete et al 2015).…”

Vav2 catalysis-dependent pathways contribute to skeletal muscle growth and metabolic homeostasis

“…18a, b). These physiological alterations, which take place at older ages than the skeletal muscle dysfunctions, recapitulate well those extensively seen in other mouse models with either reduced (in the case of Vav2 L332A/L332A mice) or increased (in the case of Vav2 Onc/Onc mice) skeletal muscle mass 12,13,15,17,18,68,75 . Many dysfunctions found in Vav2 L332A/L332A mice also resemble those found in HFD-fed WT mice (this work), further suggesting that they are caused by the progressive accumulation of body fat indirectly caused by the early alterations in muscle mass and function detected in those mice.…”

“…This indicates that the preferred fuel in these mice comes from carbohydrate sources rather than from fat. Such a shift in respiratory quotients has been observed in other mouse models with skeletal muscle hypertrophy 15,17 .…”

“…Many dysfunctions found in Vav2 L332A/L332A mice also resemble those found in HFD-fed WT mice (this work), further suggesting that they are caused by the progressive accumulation of body fat indirectly caused by the early alterations in muscle mass and function detected in those mice. According to our data and previous publications 12,13,15,17,18,68,75 , we believe that the most plausible explanation for all those late dysfunctions is that they are side effects of the signaling alterations present in the skeletal muscle of both Vav2 Onc/Onc and Vav2 L332A/L332A mice. However, we caution the readers that we cannot formally exclude the possibility that they could be the consequence of the alteration of some intrinsic functions of Vav2 in other peripheral tissues given that we have not utilized skeletal muscle-specific knock-in animals in our work.…”

“…Extensive genetic data indicate that tampering with many of the above signaling elements cause muscle atrophy, insulin resistance, type 2 diabetes, and metabolic syndrome in the case of loss-of-function events 9,12,13 . Conversely, gain-of-function changes in IGF1 pathway elements, including IGF1 itself, lead to muscle hypertrophy and protection against metabolic pathologies induced by chronic feeding on hypercaloric diets [14][15][16] . The same metabolic phenotype is observed when the muscle hypertrophy is triggered via inhibition of myostatin 17,18 .…”