Etudes sur les hormones

Regulation Hépatique de la Follistatine pendant l’effort

22/05/2019 | Etudes sur les hormones


Regulation of Hepatic Follistatin Expression at Rest and during Exercise in Mice
PEPPLER, WILLEM T       Medicine & Science in Sports & Exercise: June 2019 - Volume 51 - Issue 6 - p 1116–1125

Introduction Follistatin (FST) is a protein with numerous biological roles and was recently identified as an exercise-inducible hepatokine; however, the signals that regulate this are not well understood. The purpose of this study was to delineate potential endocrine factors that may regulate hepatic FST at rest and during exercise.

Methods This study used four experiments. First, male and female C57BL/6J mice remained sedentary or were subjected to a single bout of exercise at moderate or exhaustive intensity with liver collected immediately post. Second, mice were injected with glucagon (1 mg·kg−1, 60 min), epinephrine (2 mg·kg−1, 30 min), glucagon then epinephrine, or saline. Third, mice were pretreated with propranolol (20–60 mg·kg−1, 30 min) before epinephrine injection. Fourth, glucagon receptor wild type (Gcgr+/+) or knockout (Gcgr−/−) mice were pretreated with saline or propranolol (20 mg·kg−1, 30 min) and were subjected to a single bout of exhaustive exercise with liver collected immediately post or after 2 h recovery. In all experiments liver FST mRNA expression was measured, and in experiment four FST protein content was measured.

Results A single bout of treadmill exercise performed at an exhaustive but not moderate-intensity increased FST expression, as did injection of glucagon or epinephrine alone and when combined. Pretreatment of mice with propranolol attenuated the epinephrine-induced increase in FST expression. The exercise-induced increase in FST expression was attenuated in Gcgr−/− mice, with no effect of propranolol. Gcgr−/− mice had higher protein content of FST, but there was no effect of exercise or propranolol.

Conclusions These data suggest that both glucagon and epinephrine regulate hepatic FST expression at rest; however, only glucagon is required for the exercise-induced increase.

Comment la brûle déclenche l’anabolisme?

09/05/2019 | Etudes sur les hormones et Etudes Musculation et Etudes Compléments alimentaires


IL-6 release from muscles during exercise is stimulated by lactate-dependent protease activity
Pernille Hojman       08 MAY 2019 ajpendo

IL-6 is secreted from muscles to the circulation during high-intensity and long-duration exercise, where muscle-derived IL-6 works as an energy sensor to increase release of energy substrates from liver and adipose tissues. We investigated the mechanism involved in the exercise-mediated surge in IL-6 during exercise. Using interval-based cycling in healthy young men, swimming exercise in mice, and electrical stimulation of primary human muscle cells, we explored the role of lactate production in muscular IL-6 release during exercise. First, we observed a tight correlation between lactate production and IL-6 release during both strenuous bicycling and electrically stimulated muscle cell cultures. In mice, intramuscular injection of lactate mimicked the exercise-dependent release of IL-6, and pH buffering of lactate production during exercise attenuated IL-6 secretion. Next, we used in vivo bioimaging to demonstrate that intrinsic intramuscular proteases were activated in mice during swimming, and that blockade of protease activity blunted swimming-induced IL-6 release in mice. Last, intramuscular injection of the protease hyaluronidase resulted in dramatic increases in serum IL-6 in mice, and immunohistochemical analyses showed that intramuscular lactate and hyaluronidase injections led to release of IL-6-containing intramyocellular vesicles. We identified a pool of IL-6 located within vesicles of skeletal muscle fibers, which could be readily secreted upon protease activity. This protease-dependent release of IL-6 was initiated by lactate production, linking training intensity and lactate production to IL-6 release during strenuous exercise.

Rôle anabolique Inter-Organes du GIP

02/04/2019 | Etudes sur les hormones


A Physiological Role of Inter-Organ Network between Gastrointestine and Skeletal Muscle on the Regulation of Skeletal Muscle Volume
Katsumasa Goto     The FASEB Journal       1 Apr 2019Abstract Number:700.1

Several inter-organ networks have been proposed. In general, gastrointestinal hormone gastric inhibitory polypeptide (GIP), which is synthesized in and secreted from K cells, regulates nutrient absorption via inhibition of gastric contraction and acid secretion. GIP receptor On the other hand, GIPR expresses in not only a gastrointestinal tract but also β cells in the pancreas. Since GIP also modulates glucose metabolism via insulin synthesis and secretion, GIP is also a member of incretin. Recently, the expression of GIP is also confirmed in skeletal muscle. However, there is no evidence for the inter-organ network between gastrointestine and skeletal muscle. In the present study, we investigated a physiological role of the inter-organ network between gastrointestine and skeletal muscle via GIP. GIP stimulates myogenic differentiation of C2C12 cells. Expression of GIPR was observed in C2C12 myoblasts and myotubes. Knockdown of GIPR induced the down-regulation of Pax7 in C2C12 myoblasts. In addition, GIPR-knockdown-associated depression of myotube formation of C2C12 cells were observed. On the other hand, GIPR-knockdown stimulated proliferation of C2C12 myoblasts. Therefore, GIP-GIPR intracellular signal(s) might play a role in the regulation of skeletal muscle volume via the mediation of myogenic differentiative potential.

Rôles des polyamines dans l’action anabolique des androgènes?

02/04/2019 | Etudes sur les hormones et Etudes Compléments alimentaires


Expression of Genes that Comprise the Core Molecular Clock are Altered in the Atrophied Skeletal Muscle by Androgen Deprivation
Michael L Rossetti     The FASEB Journal       1 Apr 2019Abstract Number:579.1

Skeletal muscle atrophy increases the risk of morbidity and mortality during various pathological conditions. In males, a decrease in the production and/or bioavailability of androgens (termed hypogonadism) directly contributes to muscle atrophy during various pathological conditions. While it is known that androgens prevent muscle atrophy, the mechanism(s) by which androgens mediate this effect are largely undefined. Our laboratory previously showed that mitochondrial turnover is enhanced in the tibialis anterior (TA) muscle of mice by androgen deprivation induced by castration surgery, and the magnitude of turnover was related to the degree of muscle atrophy.

These data suggest that potentially dysfunctional mitochondria contribute to the muscle atrophy observed following androgen deprivation. To gain a better understanding of that factors that might contribute to changes in mitochondrial quality control during androgen deprived conditions, we subjected total RNA from the TA of sham and castrated mice to microarray analysis. This unbiased approach identified significant changes in expression of genes that comprise the core molecular clock. qRT-PCR confirmed that expression of Brain and Muscle Arntl 1 (Bmal1) was decreased, while expression of Period 1, Period 2, and Period 3 (Per1, 2, & 3) were increased in the TA of castrated mice. When measured across a diurnal cycle, the change in expression of Bmal1, Per1, and Per2 exhibited reduced amplitude under androgen-deprived conditions. Interestingly, strong relationships were observed between the castration-mediated changes of core clock components and the measures of mitochondrial turnover. Specifically, Bmal1 expression was directly related to BCL2/adenovirus E1B 19 kDA protein-interacting protein 3 (BNIP3) protein content (R2 = 0.88), and the expression of core clock components were also directly related to the content of various mitochondrial proteins.

Expression of core clock components were also related to the autophagy marker, p62, and the mass of the TA. Ex post facto analysis of the microarray also identified changes in genes regulating polyamine biosynthesis. As polyamines are known to alter core clock function, we determined whether androgen deprivation altered polyamine content. While castration did not alter Spermine content, there was a significant reduction in the content of Spermidine in the TA of castrated mice.

Overall, these data suggest that reduced Spermidine concentrations may contribute to alterations in the core molecular clock in the skeletal muscle under androgen-deprived conditions, which may in turn contribute to reduced mitochondrial quality control and subsequent muscle atrophy

Effets directs de l’insuline sur la force?

02/04/2019 | Etudes sur les hormones


Responses to Mechanical and Chemical Stimuli are Augmented by Insulin Administration in Neurons Innervating Skeletal Muscle
Norio Hotta     The FASEB Journal               1 Apr 2019Abstract Number:540.7

Hyperinsulinemia is known to activate the sympathetic nervous system, but the underlying mechanism remains to be elucidated. Mechanical or chemical stimuli to skeletal muscle induce sympathoexcitation via group III and group IV thin-fiber afferents. Evidence suggests that insulin both facilitates translocation of molecular candidates for mechano-gated channels and activates transient receptor potential vanilloid 1 (TRPV1) channels associated with these afferent fibers. We therefore hypothesized that insulin potentiates neural responsiveness to mechanical and chemical stimuli in thin-fiber afferents and the dorsal root ganglia (DRG) that sub-serve these neurons in skeletal muscle.

We investigated the effects of insulin administration on whole-cell current responses to mechanical/chemical stimuli in DRG neurons of normal healthy mice. Further, we examined the impact of insulin on the action potential response to mechanical/chemical stimulation in thin-fiber muscle afferents of normal healthy rats.

We performed whole cell patch-clamp recordings using cultured mice DRG neurons. Mechanical stimuli to the cell surface was applied using a stimulation probe with resultant mechanically activated (MA) currents recorded. DRG neurons were also exposed to 1μM capsaicin. Using a rat muscle-nerve preparation in vitro, we applied 1) a ramp-shaped mechanical stimulation and 2) a 1μM capsaicin stimulation to the neuron’s receptive field and measured the elicited action potential utilizing single-fiber recordings.

In cultured DRG neurons, insulin (500 mU) reduced mechanical threshold from 3.6 ± 0.4 to 2.6 ± 0.3 steps (n=17, P<0.05) and increased MA current from −93±12 to −190±43 pA (n=16, P<0.05). These changes were blocked by pretreatment with the insulin receptor inhibitor GSK1838705. Likewise, the total charge transfer induced by capsaicin activated current (fold change from baseline) was significantly higher after insulin administration (3.3±1.2, n=5) than that of control (0.5±0.2, n=6). Again, this difference was prevented by pretreatment with GSK1838705. In the muscle-nerve preparation, the mechanical threshold of thin-fiber muscle afferents was significantly decreased 10 min after insulin injection (500 mU) from 66±16 to 28±12 mN (n=10, P<0.05). This decrease was eliminated by insulin receptor blockade via GSK1838705. Insulin administration also significantly increased the response magnitude to 1μM capsaicin (from 0.05±0.08 Hz before insulin to 0.70±0.40 Hz after insulin, n=5, P<0.05).

The data demonstrate that insulin sensitizes thin fiber afferents and DRG neurons innervating skeletal muscle. Further, these findings suggest that hyperinsulinemia may induce sympathoexcitation via augmentations in the responsiveness of mechano-gated channels and TRPV1 receptors on skeletal muscle thin-fiber afferents.

La follistatine agit aussi sur l’insuline

06/03/2019 | Etudes sur les hormones


Mechanisms involved in follistatin-induced increased insulin action in skeletal muscle
Xiuquing Han     bioRxiv posted 5 March 2019

Background: Skeletal muscle wasting is often associated with insulin resistance. A major regulator of muscle mass is the transforming growth factor beta (TGF-beta) superfamily, including activin A, which causes atrophy. TGF-beta superfamily ligands also negatively regulate insulin-sensitive proteins, but whether this pathway contributes to insulin action remains to be determined.

Methods: To elucidate if TGF-beta superfamily ligands regulate insulin action we used an adeno-associated virus gene editing approach to overexpress the activin A inhibitor, follistatin (Fst288) in mouse muscle of lean and diet-induced obese mice. We determined basal and insulin-stimulated 2 deoxy-glucose uptake using isotopic tracers in vivo. Furthermore, to evaluate whether circulating Fst and activin A concentrations are associated with obesity, insulin resistance, and weight loss in humans we analysed serum from morbidly obese subjects before, 1 week, and 1 year after Roux-en-Y gastric bypass (RYGB).

Results: Fst288 muscle overexpression markedly increased in vivo insulin-stimulated (but not basal) glucose uptake (+75 percent) and increased protein expression and intracellular insulin signalling of AKT, TBC1D4, PAK1, and p70S6K. Importantly, Fst288 completely normalized muscle glucose uptake in insulin-resistant diet-induced obese mice. RYGB surgery doubled circulating Fst and reduced Activin A (-24 percent) concentration 1 week after surgery before any significant weight loss in morbidly obese normoglycemic patients, while major weight loss after 1 year did not further change the concentrations.

Conclusions: We here present evidence that Fst is a potent regulator of insulin action in muscle and in addition to AKT and p70S6K, we identify TBC1D1, TBC1D4 and PAK1 as Fst targets. A possible role for Fst in regulating glycemic control is suggested because circulating Fst more than doubled post RYGB surgery, a treatment that markedly improved insulin sensitivity. These findings demonstrate the therapeutic potential of inhibiting TGF-beta superfamily ligands to improve insulin action and Fst s relevance to insulin resistant conditions in mice and humans.

Actions santé de la mélatonine

11/01/2019 | Etudes sur les hormones et Echauffement et blessures et Etudes Compléments alimentaires et Etudes Anti-âge


The multiple protective roles and molecular mechanisms of melatonin and its precursor N-acetylserotonin in targeting brain injury and liver damage and in maintaining bone health
ChengliangLuoa       Free Radical Biology and Medicine Volume 130, January 2019, Pages 215-233

• Melatonin and NAS are protective agents for brain injury, liver damage and bone health.
• Melatonin and NAS are anti-oxidative stress and anti-inflammation.
• Melatonin and NAS are against autophagy dysfunction and anti-apoptosis.
• MT1/MT2 are needed for brain and liver injuries and MT2 is important for bone health.
• Melatonin and NAS will be likely to show utility in clinical trials.

Melatonin is a neurohormone associated with sleep and wakefulness and is mainly produced by the pineal gland. Numerous physiological functions of melatonin have been demonstrated including anti-inflammation, suppressing neoplastic growth, circadian and endocrine rhythm regulation, and its potent antioxidant activity as well as its role in regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others.

In this review, we summarize the recent advances related to the multiple protective roles of melatonin receptor agonists, melatonin and N-acetylserotonin (NAS), in brain injury, liver damage, and bone health. Brain injury, including traumatic brain injury, ischemic stroke, intracerebral hemorrhage, subarachnoid hemorrhage, and newborn perinatal hypoxia-ischemia encephalopathy, is a major cause of mortality and disability. Liver disease causes serious public health problems and various factors including alcohol, chemical pollutants, and drugs induce hepatic damage. Osteoporosis is the most common bone disease in humans. Due in part to an aging population, both the cost of care of fracture patients and the annual fracture rate have increased steadily. Despite the discrepancy in the pathophysiological processes of these disorders, time frames and severity, they may share several common molecular mechanisms. Oxidative stress is considered to be a critical factor in these pathogeneses. We update the current state of knowledge related to the molecular processes, mainly including anti-oxidative stress, anti-apoptosis, autophagy dysfunction, and anti-inflammation as well as other properties of melatonin and NAS. Particularly, the abilities of melatonin and NAS to directly scavenge oxygen-centered radicals and toxic reactive oxygen species, and indirectly act through antioxidant enzymes are disscussed. In this review, we summarize the similarities and differences in the protection provided by melatonin and/or NAS in brain, liver and bone damage.

We analyze the involvement of melatonin receptor 1A (MT1), melatonin receptor 1B (MT2), and melatonin receptor 1C (MT3) in the protection of melatonin and/or NAS. Additionally, we evaluate their potential clinical applications. The multiple mechanisms of action and multiple organ-targeted properties of melatonin and NAS may contribute to development of promising therapies for clinical trials.

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