Insulin-like growth factor-1 builds muscle (hypertrophy) and utilizes carbohydrates as fuel for energy.
[FONT=Minion W08 Regular_1167271]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.
[/FONT]1. Introduction
[FONT=Minion W08 Regular_1167271]One of the remarkable features of skeletal muscle is the capacity to adapt its metabolic and functional properties in response to a wide range of external factors, including physical and neuron activity, change in hormone levels, and oxygen and nutrient supply
However in several pathological conditions, skeletal muscle severely decreases this adaptive capacity, triggering alterations in its metabolic properties evolving to disease. In fact, insulin resistance (IR), obesity, high blood pressure, high fasting glucose or hyperglycemia, and lipid abnormalities are all conditions related to morphofunctional and metabolic changes in skeletal muscle
[/FONT][FONT=Minion W08 Regular_1167271]Recent evidences have shown that different therapeutic interventions can improve body composition and systemic metabolism
Among these, physical activity has been considered in the therapeutic effects of exercise for type II diabetes (T2DM) and other metabolic syndromes , although regular physical activity as a therapeutic tool can be seriously assumed in only a fraction of the population, mainly due to motivational and physical limitations.
From a metabolic point of view, however, it remains not well understood what molecular/cellular aspects of exercise should be mimicked and what type of muscle fiber is best targeted to improve metabolic dysfunction. Increased physical activity is usually achieved by exercise training, which can be divided into two major categories: endurance and resistance. It is well known that endurance training promotes metabolic alterations in skeletal muscle due to a shift in substrate preference as a consequence of fatty acid oxidative metabolism and muscle fiber type interconversion, resulting in a greater number of the slow twitch oxidative fibers
. In contrast, resistance training is known for its capacity to promote an increase in skeletal muscle mass (hypertrophy) and strength
. Nonetheless, the molecular factors linking skeletal muscle growth and metabolism still remain to be explored in detail. Among growth factors, the Insulin-like growth factor-1 (IGF-1) has been implicated in the control of both muscle mass and skeletal muscle homeostasis and its expression is significantly enhanced in response to exercise
.[/FONT][FONT=Minion W08 Regular_1167271]It has been previously reported that muscle restricted mIGF-1 transgene (MLC/mIGF-1) sustains muscle hypertrophy and regeneration in senescent skeletal muscle, enhances the recruitment of circulating stem cells in injured muscle and counteracts muscle wasting in mdx dystrophic mice , improving muscle mass and strength and elevating pathways associated with muscle survival and regeneration.
Although significant advances have been made with this genetic model, overall, the impact of manipulating skeletal muscle hypertrophic pathways upon whole body metabolism and glucose disposal is largely unknown.[/FONT][FONT=Minion W08 Regular_1167271]In the present study, we investigated metabolic features of MLC/mIGF-1 mice, revealing an unexpected higher respiratory quotient at rest, an index of higher carbohydrate utilization. These animals also showed higher insulin sensitivity, in line with a preference for carbohydrate as the primary energy source. In addition we have detected increased GLUT4 protein levels in skeletal muscle. These findings reinforce the potential of manipulating IGF-1 triggered intracellular pathways as therapeutic tools in the treatment of insulin resistance and type II diabetes.[/FONT]
[FONT=Minion W08 Regular_1167271]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.
[/FONT]1. Introduction
[FONT=Minion W08 Regular_1167271]One of the remarkable features of skeletal muscle is the capacity to adapt its metabolic and functional properties in response to a wide range of external factors, including physical and neuron activity, change in hormone levels, and oxygen and nutrient supply
However in several pathological conditions, skeletal muscle severely decreases this adaptive capacity, triggering alterations in its metabolic properties evolving to disease. In fact, insulin resistance (IR), obesity, high blood pressure, high fasting glucose or hyperglycemia, and lipid abnormalities are all conditions related to morphofunctional and metabolic changes in skeletal muscle
[/FONT][FONT=Minion W08 Regular_1167271]Recent evidences have shown that different therapeutic interventions can improve body composition and systemic metabolism
Among these, physical activity has been considered in the therapeutic effects of exercise for type II diabetes (T2DM) and other metabolic syndromes , although regular physical activity as a therapeutic tool can be seriously assumed in only a fraction of the population, mainly due to motivational and physical limitations.
From a metabolic point of view, however, it remains not well understood what molecular/cellular aspects of exercise should be mimicked and what type of muscle fiber is best targeted to improve metabolic dysfunction. Increased physical activity is usually achieved by exercise training, which can be divided into two major categories: endurance and resistance. It is well known that endurance training promotes metabolic alterations in skeletal muscle due to a shift in substrate preference as a consequence of fatty acid oxidative metabolism and muscle fiber type interconversion, resulting in a greater number of the slow twitch oxidative fibers
. In contrast, resistance training is known for its capacity to promote an increase in skeletal muscle mass (hypertrophy) and strength
. Nonetheless, the molecular factors linking skeletal muscle growth and metabolism still remain to be explored in detail. Among growth factors, the Insulin-like growth factor-1 (IGF-1) has been implicated in the control of both muscle mass and skeletal muscle homeostasis and its expression is significantly enhanced in response to exercise
.[/FONT][FONT=Minion W08 Regular_1167271]It has been previously reported that muscle restricted mIGF-1 transgene (MLC/mIGF-1) sustains muscle hypertrophy and regeneration in senescent skeletal muscle, enhances the recruitment of circulating stem cells in injured muscle and counteracts muscle wasting in mdx dystrophic mice , improving muscle mass and strength and elevating pathways associated with muscle survival and regeneration.
Although significant advances have been made with this genetic model, overall, the impact of manipulating skeletal muscle hypertrophic pathways upon whole body metabolism and glucose disposal is largely unknown.[/FONT][FONT=Minion W08 Regular_1167271]In the present study, we investigated metabolic features of MLC/mIGF-1 mice, revealing an unexpected higher respiratory quotient at rest, an index of higher carbohydrate utilization. These animals also showed higher insulin sensitivity, in line with a preference for carbohydrate as the primary energy source. In addition we have detected increased GLUT4 protein levels in skeletal muscle. These findings reinforce the potential of manipulating IGF-1 triggered intracellular pathways as therapeutic tools in the treatment of insulin resistance and type II diabetes.[/FONT]
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