Muscle IGF-I Research Articles

Enhancing gosling growth and secretion of somatotrophic and thyrotrophic axis hormones through egg turning during incubation

ABSTRACT 1. Growth performance of Yangzhou geese hatched from eggs with turning angles of 50° or 70° was evaluated in association with serum hormones and somatotrophic gene mRNA expression. 2. Egg turning at 70° significantly (P< 0.05) increased hatchability, gosling quality and hatching weight. Gosling post-hatch body weight, leg and breast muscle weight in the 70° turning group was significantly heavier until 50 d of age. 3. Serum concentrations of GH were significantly higher until 30 d of age in the 70° turning group goslings, and those of IGF-I and T3 were higher from hatching to 50 d of age. 4. The mRNA expression of GHRH, pituitary GH, liver and leg muscle IGF-I were all significantly higher at 1 and 30 d of age after hatch, but not at 70 d after hatch, in the 70° turning group. 5. Egg turning at 70° during incubation improves embryo and gosling quality and growth performance through up-regulation of gene expression and secretion of somatotrophic axis hormones, GHRH, GH and IGF-I, as well as T3.

Insulin-like growth factor-I biocompartmentalization across blood, interstitial fluid and muscle, before and after 3 months of chronic resistance exercise.

This investigation examined the influence of 12-week ballistic resistance training programs on the IGF-I system in circulation, interstitial fluid, and skeletal muscle, at rest and in response to acute exercise. Seventeen college-aged subjects (11 women/6 men; 21.7 ± 3.7 yr) completed an acute ballistic exercise bout before and after the training program. Blood samples were collected pre-, mid-, and postexercise and analyzed for serum total IGF-I, free IGF-I, and IGF binding proteins (IGFBPs) 1-4. Dialysate and interstitial free IGF-I were analyzed in vastus lateralis (VL) interstitial fluid collected pre- and postexercise via microdialysis. Pre- and postexercise VL muscle biopsies were analyzed for IGF-I protein expression, IGF-I receptor phosphorylation (p-IGF-IR), and AKT phosphorylation (p-AKT). Following training, basal serum IGF-I, free IGF-I, IGFBP-2, and IGFBP-3 decreased whereas IGFBP-1 and IGFBP-4 increased. Training reduced basal dialysate and interstitial free IGF-I but had no effect on basal skeletal muscle IGF-I, p-IGF-IR, or p-AKT. Acute exercise elicited transient changes in IGF-I system concentrations and downstream anabolic signaling both pre- and posttraining; training did not affect this acute exercise response. Posttraining, acute exercise-induced changes in dialysate/interstitial free IGF-I were strongly correlated with the changes in intramuscular IGF-I expression, p-IGF-IR, and p-AKT. The divergent influence of resistance training on circulating/interstitial and skeletal muscle IGF-I demonstrates the importance of concurrent, multiple biocompartment analysis when examining the IGF-I system. As training elicited muscle hypertrophy, these findings indicate that IGF-I's anabolic effects on skeletal muscle are mediated by local, rather than systemic mechanisms.NEW & NOTEWORTHY In the first investigation to assess resistance training's effects on the IGF-I system in serum, interstitial fluid, and skeletal muscle, training decreased basal circulating and interstitial IGF-I but did not alter basal intramuscular IGF-I protein activity. Posttraining, acute exercise-induced interstitial IGF-I increases were strongly correlated with intramuscular IGF-I expression and signaling. These findings highlight the importance of multibiocompartment measurement when analyzing IGF-I and suggest that IGF-I's role in hypertrophic adaptations is locally mediated.

Intramuscular fatty infiltration and physical function in controlled acromegaly.

Patients with acromegaly show musculoskeletal symptoms which may persist despite disease control. Increased i.m. fat fraction is a known cause of muscle dysfunction in several disorders. To assess the degree of fat fraction in thigh muscles of controlled acromegaly patients and its relationship with muscle dysfunction. In a cross-sectional study, we included 36 patients with controlled acromegaly and 36 matched controls. We assessed the percentage of fat fraction in each thigh muscle, using MRI 2-point Dixon sequence, and muscle performance and strength using the gait speed, timed up and go, 30-s chair stand, and hand grip strength tests. We evaluated joint symptoms using the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC). Intramuscular fat fraction was greater in patients than controls (P < 0.05 for muscle compartments, rectus femoris (RF), vastus intermedius (VI), adductor magnus (AM) and semimembranosus). Patients had slower gait speed and poorer performance on the 30-s chair stand and timed up and go tests than controls (P < 0.05). The greater fat fraction in the combined anterior-posterior compartment and in each muscle was associated with worse performance on timed up and go (P < 0.05). The fat fraction in the anterior-posterior compartment predicted performance on timed up and go after adjusting for muscle area, IGF-I and WOMAC functional and pain scores (β = 0.737 P < 0.001). Patients with controlled acromegaly have greater thigh i.m. fatty infiltration, which is associated with muscle dysfunction. Futures studies are needed to elucidate the mechanisms underlying this relationship.

The Dietary Lipid Content Affects the Tissue Gene Expression of Muscle Growth Biomarkers and the GH/IGF System of Pejerrey (Odontesthes bonariensis) Juveniles

Gene expression of growth hormone receptors (GHRs), insulin-like growth factors (IGFs), myostatin (MSTN) and myogenin (MyoG) was analyzed in juveniles pejerrey fed with graded levels of lipids (L): 6% (L6), 10% (L10), 25% (L25). After 14 weeks, no changes were found in liver GHR-I GHR-II and IGF-II mRNA levels whereas IGF-I decreased in L10 and L25. Muscle GHR-I gene expression increased in L25 whereas GHR-II, IGF-II and MyoG were higher in L6. IGF-I and MSTN expression was not affected by the different diets. Adipose IGF-I mRNA levels decreased in L10. Correlations between body weight and members of GH/IGF system in liver and skeletal muscle were found only in L10 group. Correlations found in L10 group between both liver and skeletal muscle GHR-I and IGF-I were lost in either L6 or L25 groups. Thus, fish fed with apparently unbalanced dietary lipid contents (6% and 25%) exhibit a compensatory regulation of systemic and local components of the GH/IGF axis. Furthermore, the marked inhibition of muscle MyoG gene expression in L25 might limit excessive lipid deposition and fish growth. Our data suggest that a dietary lipid contents of 10% would promote a particular adjustment of the endocrine and autocrine/paracrine GH/IGF system, stimulating body growth and perhaps muscle hyperplasia. On the other hand, a higher dietary lipid content would uncouple the GH/IGF system, reducing hepatic IGF-I, while slightly increasing hepatic GHR-I, probably to prompt lipolysis.

PO-071 Effects of Resistance Training of Different Loads on Gastrocnemius Protein, IGF-I and TNF-α in Aging Rats

Objective To observe the effects of different load resistance training on skeletal muscle dystrophy in aging rats by observing the expression of protein and protein of IGF-I and TNF-α in aging rats after 8 weeks of different load resistance training. The resistance training delays the theoretical basis for anti-skeletal muscle aging.&#x0D; Methods 40 aging SD rats (18 months old) were randomly divided into a quiet control group, a non-weight-bearing exercise group, 30% of the largest negative recombination, 50% of the largest negative recombination, and 70% of the largest negative recombination. The sports group carried the treadmill movement with the tail load, the slope was 35°, the running speed was 15m/min, the rest was 30s every 15s, the rest was 3min after four cycles, and the three groups were one cycle. The cycle was intermittent for 10 minutes, and the exercise frequency was the next day for 8 weeks. After 8 weeks, the rat gastrocnemius muscle was taken. The protein content of the gastrocnemius muscle was determined by Coomassie brilliant blue method. The contents of IGF-I and TNF-α in the gastrocnemius muscle were determined by enzyme-linked immunosorbent assay.&#x0D; Results After 1.8 weeks of different load resistance exercise, compared with the quiet control group, the skeletal muscle protein content of each exercise group increased, among which 50% of the largest negative recombination and 70% of the largest negative recombination was the most significant (P&lt;0.01). Compared with 70% of the largest negative recombination, the 50% maximum negative recombination content was relatively high (P&lt;0.05);&#x0D; &#x0D; After 8 weeks of different load resistance exercise, compared with the quiet control group, the content of IGF-I in the gastrocnemius of each exercise group was higher than that of the quiet control group, and there was a very significant difference (P&lt;0.01), and 50%. The highest negative recombination and 70% of the largest negative recombination content is the highest;&#x0D; After 8 weeks of different load resistance exercise, compared with the quiet control group, the TNF-α content in the gastrocnemius muscle of the rats in each resistance exercise group increased slightly, and the increase of only 50% of the largest negative recombination was statistically significant (P&lt;0.05), although there were differences between the exercise groups, there was no statistical significance (P&gt;0.05).&#x0D; &#x0D; Conclusions 50% of the maximum weight-bearing resistance training can effectively increase the skeletal muscle muscle protein content of aging SD rats, and it is related to up-regulation of IGF-I factor and down-regulation of TNF-α factor expression by resistance training.

Deletion of muscle IGF-I transiently impairs growth and progressively disrupts glucose homeostasis in male mice.

Insulin-like growth factors (IGFs) are essential for local skeletal muscle growth and organismal physiology, but these actions are entwined with glucose homeostasis through convergence with insulin signaling. The objective of this work was to determine whether the effects of IGF-I on growth and metabolism could be separated. We generated muscle-specific IGF-I-deficient (MID) mice that afford inducible deletion of Igf1 at any age. After Igf1 deletion at birth or in young adult mice, evaluations of muscle physiology and glucose homeostasis were performed up to 16 wk of age. MID mice generated at birth had lower muscle and circulating IGF-I, decreased muscle and body mass, and impaired muscle force production. Eight-wk-old male MID had heightened insulin levels with trends of elevated fasting glucose. This phenotype progressed to impaired glucose handling and increased fat deposition without significant muscle mass loss at 16 wk of age. The same phenotype emerged in 16-wk-old MID mice induced at 12 wk of age, compounded with heightened muscle fatigability and exercise intolerance. We assert that muscle IGF-I independently modulates anabolism and metabolism in an age-dependent manner, thus positioning muscle IGF-I maintenance to be critical for both muscle growth and metabolic homeostasis.-Vassilakos, G., Lei, H., Yang, Y., Puglise, J., Matheny, M., Durzynska, J., Ozery, M., Bennett, K., Spradlin, R., Bonanno, H., Park, S., Ahima, R. S., Barton, E. R. Deletion of muscle IGF-I transiently impairs growth and progressively disrupts glucose homeostasis in male mice.

Functional characterization of insulin-like growth factors in an ancestral fish species, the Shovelnose sturgeon Scaphirhynchus platorhynchus

Observations from the present study provide the first characterization of the GH-IGF axis in Shovelnose sturgeon Scaphirhynchus platorhynchus, an ancestral fish species. An initial characterization of steady-state IGF-I and IGF-II gene expression in multiple tissues was conducted using real-time RT-qPCR. Overall, the tissues had significantly different profiles of IGF-I gene expression, with the highest IGF-I expression observed in the liver. The highest IGF-II gene expression was also observed in the liver, with minimal or no detection in muscle. A comparison between IGF-I and IGF-II expression within individual tissues revealed higher levels of IGF-II than IGF-I mRNA in the spleen, stomach and trunk kidney, and higher levels of relative IGF-I mRNA expression in the intestine and muscle. The GH-IGF axis was further elucidated by observing the effects of exogenous GH on IGF-I and IGF-II expression in liver and muscle tissue. The results revealed a significant dose-dependent response of both hepatic IGF-I and IGF-II, and muscle IGF-I mRNA expression following rbGH administration. At the highest rbGH concentration (240μg/g BW), IGF-I mRNA levels in liver and muscle peaked significantly at 48h, indicating both hepatic and muscle IGF-I expression to be stimulated by GH. Hepatic IGF-II expression was also stimulated 48h following rbGH administration. Expression of IGF-II mRNA was not inducible in the muscle. Few studies have evaluated the effects of exogenous GH on IGF expression in ancestral vertebrate species, and as such, this research provides valuable insight into the evolution of the somatotropic axis in vertebrates.

The Development of Macrophage-Mediated Cell Therapy to Improve Skeletal Muscle Function after Injury.

Skeletal muscle regeneration following acute injury is a multi-step process involving complex changes in tissue microenvironment. Macrophages (MPs) are one of the key cell types involved in orchestration and modulation of the repair process. Multiple studies highlight the essential role of MPs in the control of the myogenic program and inflammatory response during skeletal muscle regeneration. A variety of MP phenotypes have been identified and characterized in vitro as well as in vivo. As such, MPs hold great promise for cell-based therapies in the field of regenerative medicine. In this study we used bone-marrow derived in vitro LPS/IFN-y-induced M1 MPs to enhance functional muscle recovery after tourniquet-induced ischemia/reperfusion injury (TK-I/R). We detected a 15% improvement in specific tension and force normalized to mass after M1 (LPS/IFN-γ) MP transplantation 24 hours post-reperfusion. Interestingly, we found that M0 bone marrow-derived unpolarized MPs significantly impaired muscle function highlighting the complexity of temporally coordinated skeletal muscle regenerative program. Furthermore, we show that delivery of M1 (LPS/IFN-γ) MPs early in regeneration accelerates myofiber repair, decreases fibrotic tissue deposition and increases whole muscle IGF-I expression.

FNDC5 relates to skeletal muscle IGF-I and mitochondrial function and gene expression in obese men with reduced growth hormone

ObjectiveTo investigate the relationship of skeletal muscle FNDC5 mRNA expression and circulating irisin to the GH/IGF-I axis and to skeletal muscle mitochondrial function and mitochondria-related gene expression in obese men. DesignFifteen abdominally obese men with reduced growth hormone received 12weeks of recombinant human GH (rhGH). Before and after treatment, they underwent 31P-magnetic resonance spectroscopy to evaluate phosphocreatine (PCr) recovery as a measure of mitochondrial function and skeletal muscle biopsy to assess expression of mitochondrial-related genes. Serum irisin and IGF-I and skeletal muscle FNDC5 and IGF-I mRNA were measured. ResultsAt baseline, skeletal muscle FNDC5 mRNA was significantly and positively associated with IGF-I mRNA (ρ=0.81, P=0.005) and rate of PCr recovery (ρ=0.79, P=0.006). Similar relationships of circulating irisin to IGF-I mRNA (ρ=0.63, P=0.05) and rate of PCr recovery (ρ=0.48, P=0.08) were demonstrated, but were not as robust as those with muscle FNDC5 expression. Both serum irisin and skeletal muscle FNDC5 mRNA were significantly associated with PPARγ (ρ=0.73, P=0.02 and ρ=0.85, P=0.002), respectively. In addition, FNDC5 mRNA was correlated with skeletal muscle PGC-1α (ρ=0.68, P=0.03), NRF1 (ρ=0.66, P=0.04) and TFAM (ρ=0.79, P=0.007) mRNA. Neither serum irisin nor muscle mRNA expression of FNDC5 changed with rhGH treatment. ConclusionThese novel data in skeletal muscle demonstrate that local expression of FNDC5 is associated with mRNA expression of IGF-I and mitochondrial function and mitochondria-related gene expression in obese subjects with reduced growth hormone and suggest a potential role for FNDC5 acting locally in muscle in a low GH state. Further studies are needed to clarify the relationship between the GH/IGF-I axis and irisin.

Role of IGF-I in follistatin-induced skeletal muscle hypertrophy.

Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth.

The effects of ovariectomy on meat performance and expression of GH/IGF-I in young goats

Zhang, L., Wang, Y.-y., Fu, M.-z., Li, G., An, N., Li, S.-y. and Zhou, Z.-q. 2014. The effects of ovariectomy on meat performance and expression of GH/IGF-I in young goats. Can. J. Anim. Sci. 94: 619–626. Experiments were carried out to investigate the effects of ovariectomy on meat production efficiency and to explore the expression of GH/IGF-I in young goats. Animal performance, meat quality, levels of serum growth hormone (GH) and insulin-like growth factor 1 (IGF-I), and mRNA levels of three key genes [GH Receptor (GHR), IGF-I and IGF-I Receptor (IGF-IR)] in longissimus dorsi and biceps femoris muscles were measured. The results show that carcass weight, net meat mass, fat weight and loin eye area of ovariectomized goats were higher than those of the controls, and ovariectomized goats lost 0.40 kg of bone weight (P&lt;0.05). There was no statistically valid difference for the color, pH, water-holding capacity, or cooking rate of meat (P&gt;0.05) between the two groups, except for the shear value, which was significantly lower in the Ovx group than in the control group (P&lt;0.05). The results of this research show for the first time a significant trend (P&lt;0.05) for serum GH and IGF-I in the direction of increasing in ovariectomized goats. Furthermore, the mRNA levels of GHR, IGF-I and IGF-IR in muscle were all up-regulated, except for the IGF-I gene in biceps femoris, by ovariectomy. In summary, ovariectomy showed a beneficial promotion in animal performance, but did not reduce meat quality, and increased serum GH and IGF-I and mRNA expression levels of GHR, IGF-I and IGF-IR in young female goats.

Resistance Training With Excessive Training Load and Insufficient Recovery Alters Skeletal Muscle Mass–Related Protein Expression

The aim of this study was to investigate the effects of a resistance training program with excessive training load and insufficient recovery time between bouts on muscle hypertrophy- and atrophy-related protein expression. Male Wistar rats were randomly assigned to either a trained (TR, N = 9) or a sedentary (SE, N = 9) group. The TR group was subjected to a 12-week resistance training program with excessive training load and insufficient recovery between bouts that was designed to induce plantaris muscle atrophy. After the 12-week experiment, the plantaris muscle was collected to analyze the cross-sectional area (CSA) of the muscle fibers, and MAFbx, MyoD, myogenin, and IGF-I protein expression (Western blot). The CSA was reduced significantly (-17%, p ≤ 0.05) in the TR group compared with the SE group. Reciprocally, there was a significant (p ≤ 0.05) 20% increase in MAFbx protein expression, whereas the MyoD (-27%), myogenin (-29%), and IGF-I (-43%) protein levels decreased significantly (p ≤ 0.05) in the TR group compared with the SE group. In conclusion, our data indicated that muscle atrophy induced by resistance training with excessive training load and insufficient recovery was associated with upregulation of the MAFbx catabolic protein and downregulation of the MyoD, myogenin, and IGF-I anabolic proteins. These findings suggest that quantitative analysis of these proteins can be important and complementary with other biochemical markers to confirm a possible overtraining diagnosis.

Erratum to: Acute mechanical overload increases IGF-I and MMP-9 mRNA in 3D tissue-engineered skeletal muscle

Erratum to: Acute mechanical overload increases IGF-I and MMP-9 mRNA in 3D tissue-engineered skeletal muscle

Acute mechanical overload increases IGF-I and MMP-9 mRNA in 3D tissue-engineered skeletal muscle

Skeletal muscle (SkM) is a tissue that responds to mechanical load following both physiological (exercise) or pathophysiological (bed rest) conditions. The heterogeneity of human samples and the experimental and ethical limitations of animal studies provide a rationale for the study of SkM plasticity in vitro. Many current in vitro approaches of mechanical loading of SkM disregard the three-dimensional (3D) structure in vivo. Tissue engineered 3D SkM, that displays highly aligned and differentiated myotubes, was used to investigate mechano-regulated gene transcription of genes implicated in hypertrophy/atrophy. Static loading (STL) and ramp loading (RPL) at 10 % strain for 60 min were used as mechano-stimulation with constructs sampled immediately for RNA extraction. STL increased IGF-I mRNA compared to both RPL and CON (control, p = 0.003 and 0.011 respectively) whilst MMP-9 mRNA increased in STL and RPL compared to CON (both p < 0.05). IGFBP-2 mRNA was differentially regulated in RPL and STL compared to CON (p = 0.057), whilst a reduction in IGFBP-5 mRNA was found for STL and RPL compared to CON (both p < 0.05). There was no effect in the expression of putative atrophic genes, myostatin, MuRF-1 and MAFBx (all p > 0.05). These data demonstrate a transcriptional signature associated with SkM hypertrophy within a tissue-engineered model that more greatly recapitulates the in vivo SkM structure compared previously published studies.

Effects of different dietary intake on mRNA levels of MSTN, IGF-I, and IGF-II in the skeletal muscle of Dorper and Hu sheep hybrid F1 rams.

MSTN, IGF-І(insulin-like growth factor-І) and IGF-II (insulin-like growth factor-II) regulate skeletal muscle growth. This study investigated the effects of different dietary intake levels on skeletal muscles. Sheep was randomly assigned to 3 feeding groups: 1) the maintenance diet (M), 2) 1.4 x the maintenance diet (1.4M), and 3) 2.15 x the maintenance diet (2.15M). Before slaughtering the animals, blood samples were collected to measure plasma urea, growth hormone, and insulin concentrations. After slaughtering, the longissimus dorsi, semitendinosus, semimembranosus, gastrocnemius, soleus, and chest muscle were removed to record various parameters, including the mRNA expression levels of MSTN and IGFs, in addition to skeletal muscle fiber diameter and cross-sectional area. The result showed that as dietary intake improved, the mRNA expression levels of MSTN and IGF-II decreased, whereas IGF-Іexpression increased. The mRNA expression levels of MSTN and IGFs were significantly different in the same skeletal muscle under different dietary intake. The skeletal muscle fiber diameter and cross-sectional area increased with greater dietary intake, as observed for the mRNA expression of IGF-І; however, it contrasted to that observed for the mRNA expression of MSTN and IGF-II. In conclusion, dietary intake levels have a certain influence on MSTN and IGFs mRNA expression levels, in addition to skeletal muscle fiber diameter and cross-sectional area. This study contributes valuable information for enhancing the molecular-based breeding of sheep.

Growth Hormone Secretion Is Correlated With Neuromuscular Innervation Rather Than Motor Neuron Number in Early-Symptomatic Male Amyotrophic Lateral Sclerosis Mice

GH deficiency is thought to be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). However, therapy with GH and/or IGF-I has not shown benefit. To gain a better understanding of the role of GH secretion in ALS pathogenesis, we assessed endogenous GH secretion in wild-type and hSOD1(G93A) mice throughout the course of ALS disease. Male wild-type and hSOD1(G93A) mice were studied at the presymptomatic, onset, and end stages of disease. To assess the pathological features of disease, we measured motor neuron number and neuromuscular innervation. We report that GH secretion profile varies at different stages of disease progression in hSOD1(G93A) mice; compared with age-matched controls, GH secretion is unchanged prior to the onset of disease symptoms, elevated at the onset of disease symptoms, and reduced at the end stage of disease. In hSOD1(G93A) mice at the onset of disease, GH secretion is positively correlated with the percentage of neuromuscular innervation but not with motor neuron number. Moreover, this occurs in parallel with an elevation in the expression of muscle IGF-I relative to controls. Our data imply that increased GH secretion at symptom onset may be an endogenous endocrine response to increase the local production of muscle IGF-I to stimulate reinnervation of muscle, but that in the latter stages of disease this response no longer occurs.

Role of IGF-I and the TNFα/NF-κB pathway in the induction of muscle atrogenes by acute inflammation

Several catabolic states (sepsis, cancer, etc.) associated with acute inflammation are characterized by a loss of skeletal muscle due to accelerated proteolysis. The main proteolytic systems involved are the autophagy and the ubiquitin-proteasome (UPS) pathways. Among the signaling pathways that could mediate proteolysis induced by acute inflammation, the transcription factor NF-κB, induced by TNFα, and the transcription factor forkhead box O (FOXO), induced by glucocorticoids (GC) and inhibited by IGF-I, are likely to play a key role. The aim of this study was to identify the nature of the molecular mediators responsible for the induction of these muscle proteolytic systems in response to acute inflammation caused by LPS injection. LPS injection robustly stimulated the expression of several components of the autophagy and the UPS pathways in the skeletal muscle. This induction was associated with a rapid increase of circulating levels of TNFα together with a muscular activation of NF-κB followed by a decrease in circulating and muscle levels of IGF-I. Neither restoration of circulating IGF-I nor restoration of muscle IGF-I levels prevented the activation of autophagy and UPS genes by LPS. The inhibition of TNFα production and muscle NF-κB activation, respectively by using pentoxifilline and a repressor of NF-κB, did not prevent the activation of autophagy and UPS genes by LPS. Finally, inhibition of GC action with RU-486 blunted completely the activation of these atrogenes by LPS. In conclusion, we show that increased GC production plays a more crucial role than decreased IGF-I and increased TNFα/NF-κB pathway for the induction of the proteolytic systems caused by acute inflammation.

Deletion of muscle GRP94 impairs both muscle and body growth by inhibiting local IGF production

Insulin-like growth factors (IGFs) are critical for development and growth of skeletal muscles, but because several tissues produce IGFs, it is not clear which source is necessary or sufficient for muscle growth. Because it is critical for production of both IGF-I and IGF-II, we ablated glucose-regulated protein 94 (GRP94) in murine striated muscle to test the necessity of local IGFs for normal muscle growth. These mice exhibited smaller skeletal muscles with diminished IGF contents but with normal contractile function and no apparent endoplasmic reticulum stress response. This result shows that muscles rely on GRP94 primarily to support local production of IGFs, a pool that is necessary for normal muscle growth. In addition, body weights were ∼30% smaller than those of littermate controls, and circulating IGF-I also decreased significantly, yet glucose homeostasis was maintained with little disruption to the growth hormone pathway. The growth defect was complemented on administration of recombinant IGF-I. Thus, unlike liver production of IGF-I, muscle IGF-I is necessary not only locally but also globally for whole-body growth.

Short-term growth hormone or IGF-I administration improves the IGF-IGFBP system in arthritic rats

ObjectiveAdjuvant-induced arthritis is an experimental model of rheumatoid arthritis that inhibits the GH-IGF-I axis and decreases body weight gain and muscle mass. Although chronic GH or IGF-I treatment increases body weight gain in arthritic rats, muscle resistance to GH and IGF-I is a very common complication in inflammatory diseases. In this study we examine the effect of short-term administration of rhGH and rhIGF-I on liver and muscle IGF-I, IGFBP-3 and −5 as well as on the ubiquitin-ligases MuRF1 and atrogin-1 in the muscle of arthritic rats. DesignArthritis was induced in adult male Wistar rats by an intradermal injection of 4mg of Freund's adjuvant. Fifteen days after adjuvant injection, 300μg/kg of rhGH or 200μg/kg of rhIGF or saline was administrated 18 and 3h before decapitation. A pair-fed group injected with saline was included in order to discard a possible effect of decreased food intake. Gene expression of IGF-I, GHR, IGFBP-3, IGFBP-5, atrogin-1 and MuRF1 were quantified using RT-PCR. In serum, IGF-I was measured by radioimmunoassay (RIA) and IGFBP-3 by ligand blot. ResultsArthritis decreased serum IGF-I and IGF mRNA in liver (P<0.05), but not in skeletal muscle. In arthritic rats, rhGH increased serum IGF-I and liver IGF-I mRNA similar to the levels of pair-fed rats. Arthritis increased atrogin-1, MuRF1, IGFBP-3 and IGFBP-5 mRNA in muscle (P<0.01). IGFBP-3 mRNA was downregulated by rhIGF-I, but not by rhGH, administration in control and arthritic rats (P<0.05). Administration of rhGH and rhIGF-I increased IGFBP-5 in the gastrocnemius of arthritic rats. ConclusionsShort-term rhGH and rhIGF-I administration was found to increase muscle IGFBP-5 mRNA, whereas only rhIGF-I administration decreased muscle IGFBP-3 mRNA in control and arthritic rats. These data suggest that arthritis does not induce GH or IGF-I resistance in skeletal muscle.

Endocrine Characterization of the Designer Steroid Methyl-1-Testosterone: Investigations on Tissue-Specific Anabolic-Androgenic Potency, Side Effects, and Metabolism

Various products containing rarely characterized anabolic steroids are nowadays marketed as dietary supplements. Herein, the designer steroid methyl-1-testosterone (M1T) (17β-hydroxy-17α-methyl-5α-androst-1-en-3-one) was identified, and its biological activity, potential adverse effects, and metabolism were investigated. The affinity of M1T toward the androgen receptor (AR) was tested in vitro using a yeast AR transactivation assay. Its tissue-specific androgenic and anabolic potency and potential adverse effects were studied in a Hershberger assay (sc or oral), and tissue weights and selected molecular markers were investigated. Determination of M1T and its metabolites was performed by gas chromatography mass spectrometry. In the yeast AR transactivation assay, M1T was characterized as potent androgen. In rats, M1T dose-dependently stimulated prostate and levator ani muscle weight after sc administration. Oral administration had no effect but stimulated proliferation in the prostate and modulated IGF-I and AR expression in the gastrocnemius muscle in a dose-dependent manner. Analysis of tyrosine aminotransferase expression provided evidence for a strong activity of M1T in the liver (much higher after oral administration). In rat urine, 17α-methyl-5α-androstane-3α,17β-diol, M1T, and a hydroxylated metabolite were identified. In humans, M1T was confirmed in urine in addition to its main metabolites 17α-methyl-5α-androst-1-ene-3α,17β-diol and 17α-methyl-5α-androstane-3α,17β-diol. Additionally, the corresponding 17-epimers as well as 17β-hydroxymethyl-17α-methyl-18-nor-5α-androsta-1,13-dien-3-one and its 17-epimer were detected, and their elimination kinetics was monitored. It was demonstrated that M1T is a potent androgenic and anabolic steroid after oral and sc administration. Obviously, this substance shows no selective AR modulator characteristics and might exhibit liver toxicity, especially after oral administration.