Muscle protein synthesis, mTORC1/MAPK/Hippo signaling, and capillary density are altered by blocking of myostatin and activins

2013 ◽  
Vol 304 (1) ◽  
pp. E41-E50 ◽  
Author(s):  
Juha J. Hulmi ◽  
Bernardo M. Oliveira ◽  
Mika Silvennoinen ◽  
Willem M. H. Hoogaars ◽  
Hongqiang Ma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Capillary Density ◽  
Mapk Signaling ◽  
Muscle Size ◽  
Mdx Mice ◽  
Hippo Signaling ◽  
Mtorc1 Signaling

Loss of muscle mass and function occurs in various diseases. Myostatin blocking can attenuate muscle loss, but downstream signaling is not well known. Therefore, to elucidate associated signaling pathways, we used the soluble activin receptor IIb (sActRIIB-Fc) to block myostatin and activins in mice. Within 2 wk, the treatment rapidly increased muscle size as expected but decreased capillary density per area. sActRIIB-Fc increased muscle protein synthesis 1–2 days after the treatment correlating with enhanced mTORC1 signaling (phosphorylated rpS6 and S6K1, r = 0.8). Concurrently, increased REDD1 and eIF2Bε protein contents and phosphorylation of 4E-BP1 and AMPK was observed. In contrast, proangiogenic MAPK signaling and VEGF-A protein decreased. Hippo signaling has been characterized recently as a regulator of organ size and an important regulator of myogenesis in vitro. The phosphorylation of YAP (Yes-associated protein), a readout of activated Hippo signaling, increased after short- and longer-term myostatin and activin blocking and in exercised muscle. Moreover, dystrophic mdx mice had elevated phosphorylated and especially total YAP protein content. These results show that the blocking of myostatin and activins induce rapid skeletal muscle growth. This is associated with increased protein synthesis and mTORC1 signaling but decreased capillary density and proangiogenic signaling. It is also shown for the first time that Hippo signaling is activated in skeletal muscle after myostatin blocking and exercise and also in dystrophic muscle. This suggests that Hippo signaling may have a role in skeletal muscle in various circumstances.

scholarly journals Insulin Stimulates Human Skeletal Muscle Protein Synthesis via an Indirect Mechanism Involving Endothelial-Dependent Vasodilation and Mammalian Target of Rapamycin Complex 1 Signaling

2010 ◽  
Vol 24 (6) ◽  
pp. 1306-1306
Author(s):  
Kyle L. Timmerman ◽  
Jessica L. Lee ◽  
Hans C. Dreyer ◽  
Shaheen Dhanani ◽  
Erin L. Glynn ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Skeletal Muscle Protein ◽  
Capillary Recruitment ◽  
Isotope Tracers ◽  
Skeletal Muscle Protein Synthesis ◽  
Mtorc1 Signaling

Abstract Objective: Our objective was to determine whether endothelial-dependent vasodilation is an essential mechanism by which insulin stimulates human skeletal muscle protein synthesis and anabolism. Subjects: Subjects were healthy young adults (n = 14) aged 31 ± 2 yr. Design: Subjects were studied at baseline and during local leg infusion of insulin alone (control, n = 7) or insulin plus the nitric oxide synthase inhibitor NG-monomethyl-l-arginine (L-NMMA, n = 7) to prevent insulin-induced vasodilation. Methods: We measured skeletal muscle protein metabolism with stable isotope tracers, blood flow with indocyanine green, capillary recruitment with contrast enhanced ultrasound, glucose metabolism with stable isotope tracers, and phosphorylation of proteins associated with insulin (Akt) and amino acid-induced mammalian target of rapamycin(mTOR) complex 1 (mTORC1) signaling (mTOR, S6 kinase 1, and eukaryotic initiation factor 4Ebinding protein 1) with Western blot analysis. Results: No basal differences between groups were detected. During insulin infusion, blood flow and capillary recruitment increased in the control (P < 0.05) group only; Akt phosphorylation and glucose uptake increased in both groups (P < 0.05), with no group differences; and mTORC1 signaling increased more in control (P < 0.05) than in l-NMMA. Phenylalanine net balance increased (P < 0.05) in both groups, but with opposite mechanisms: increased protein synthesis (basal, 0.051 ± 0.006%/h; insulin, 0.077 ± 0.008%/h; P < 0.05) with no change in proteolysis in control and decreased proteolysis (P < 0.05) with no change in synthesis (basal, 0.061 ± 0.004%/h; insulin, 0.050 ± 0.006%/h; P value not significant) in l-NMMA. Conclusions: Endothelial-dependent vasodilation and the consequent increase in nutritive flow and mTORC1 signaling, rather than Akt signaling, are fundamental mechanisms by which insulin stimulates muscle protein synthesis in humans. Additionally, these data underscore that insulin modulates skeletal muscle proteolysis according to its effects on nutritive flow.

scholarly journals The Paradoxical Effect of PARP Inhibitor BGP-15 on Irinotecan-Induced Cachexia and Skeletal Muscle Dysfunction

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3810
Author(s):  
Dean G. Campelj ◽  
Cara A. Timpani ◽  
Aaron C. Petersen ◽  
Alan Hayes ◽  
Craig A. Goodman ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Adjuvant Therapy ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Parp Inhibitor ◽  
Force Production ◽  
Musculotendinous Junction ◽  
Skeletal Myopathy ◽  
Mtorc1 Signaling

Chemotherapy-induced muscle wasting and dysfunction is a contributing factor to cachexia alongside cancer and increases the risk of morbidity and mortality. Here, we investigate the effects of the chemotherapeutic agent irinotecan (IRI) on skeletal muscle mass and function and whether BGP-15 (a poly-(ADP-ribose) polymerase-1 (PARP-1) inhibitor and heat shock protein co-inducer) adjuvant therapy could protect against IRI-induced skeletal myopathy. Healthy 6-week-old male Balb/C mice (n = 24; 8/group) were treated with six intraperitoneal injections of either vehicle, IRI (30 mg/kg) or BGP-15 adjuvant therapy (IRI+BGP; 15 mg/kg) over two weeks. IRI reduced lean and tibialis anterior mass, which were attenuated by IRI+BGP treatment. Remarkably, IRI reduced muscle protein synthesis, while IRI+BGP reduced protein synthesis further. These changes occurred in the absence of a change in crude markers of mammalian/mechanistic target of rapamycin (mTOR) Complex 1 (mTORC1) signaling and protein degradation. Interestingly, the cytoskeletal protein dystrophin was reduced in both IRI- and IRI+BGP-treated mice, while IRI+BGP treatment also decreased β-dystroglycan, suggesting significant remodeling of the cytoskeleton. IRI reduced absolute force production of the soleus and extensor digitorum longus (EDL) muscles, while IRI+BGP rescued absolute force production of the soleus and strongly trended to rescue force output of the EDL (p = 0.06), which was associated with improvements in mass. During the fatiguing stimulation, IRI+BGP-treated EDL muscles were somewhat susceptible to rupture at the musculotendinous junction, likely due to BGP-15’s capacity to maintain the rate of force development within a weakened environment characterized by significant structural remodeling. Our paradoxical data highlight that BGP-15 has some therapeutic advantage by attenuating IRI-induced skeletal myopathy; however, its effects on the remodeling of the cytoskeleton and extracellular matrix, which appear to make fast-twitch muscles more prone to tearing during contraction, could suggest the induction of muscular dystrophy and, thus, require further characterization.

scholarly journals Insulin Stimulates Human Skeletal Muscle Protein Synthesis via an Indirect Mechanism Involving Endothelial-Dependent Vasodilation and Mammalian Target of Rapamycin Complex 1 Signaling

2010 ◽  
Vol 95 (8) ◽  
pp. 3848-3857 ◽  
Author(s):  
Kyle L. Timmerman ◽  
Jessica L. Lee ◽  
Hans C. Dreyer ◽  
Shaheen Dhanani ◽  
Erin L. Glynn ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mammalian Target Of Rapamycin ◽  
Skeletal Muscle Protein ◽  
Capillary Recruitment ◽  
Isotope Tracers ◽  
Skeletal Muscle Protein Synthesis ◽  
Mtorc1 Signaling

Objective: Our objective was to determine whether endothelial-dependent vasodilation is an essential mechanism by which insulin stimulates human skeletal muscle protein synthesis and anabolism. Subjects: Subjects were healthy young adults (n = 14) aged 31 ± 2 yr. Design: Subjects were studied at baseline and during local leg infusion of insulin alone (control, n = 7) or insulin plus the nitric oxide synthase inhibitor NG-monomethyl-l-arginine (l-NMMA, n = 7) to prevent insulin-induced vasodilation. Methods: We measured skeletal muscle protein metabolism with stable isotope tracers, blood flow with indocyanine green, capillary recruitment with contrast enhanced ultrasound, glucose metabolism with stable isotope tracers, and phosphorylation of proteins associated with insulin (Akt) and amino acid-induced mammalian target of rapamycin (mTOR) complex 1 (mTORC1) signaling (mTOR, S6 kinase 1, and eukaryotic initiation factor 4E-binding protein 1) with Western blot analysis. Results: No basal differences between groups were detected. During insulin infusion, blood flow and capillary recruitment increased in the control (P < 0.05) group only; Akt phosphorylation and glucose uptake increased in both groups (P < 0.05), with no group differences; and mTORC1 signaling increased more in control (P < 0.05) than in l-NMMA. Phenylalanine net balance increased (P < 0.05) in both groups, but with opposite mechanisms: increased protein synthesis (basal, 0.051 ± 0.006 %/h; insulin, 0.077 ± 0.008 %/h; P < 0.05) with no change in proteolysis in control and decreased proteolysis (P < 0.05) with no change in synthesis (basal, 0.061 ± 0.004 %/h; insulin, 0.050 ± 0.006 %/h; P value not significant) in l-NMMA. Conclusions: Endothelial-dependent vasodilation and the consequent increase in nutritive flow and mTORC1 signaling, rather than Akt signaling, are fundamental mechanisms by which insulin stimulates muscle protein synthesis in humans. Additionally, these data underscore that insulin modulates skeletal muscle proteolysis according to its effects on nutritive flow.

scholarly journals Disruption of REDD1 gene ameliorates sepsis-induced decrease in mTORC1 signaling but has divergent effects on proteolytic signaling in skeletal muscle

2015 ◽  
Vol 309 (12) ◽  
pp. E981-E994 ◽  
Author(s):  
Jennifer L. Steiner ◽  
Kristen T. Crowell ◽  
Scot R. Kimball ◽  
Charles H. Lang
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Cecal Ligation ◽  
Skeletal Muscle Atrophy ◽  
Matched Pair ◽  
Mtorc1 Signaling ◽  
Ubiquitin Proteasome ◽  
Lysosomal System

Sepsis-induced skeletal muscle atrophy and weakness are due in part to decreased mTORC1-mediated protein synthesis and increased proteolysis via the autophagy-lysosomal system and ubiquitin-proteasome pathway. The REDD1 (regulated in development and DNA damage-1) protein is increased in sepsis and can negatively regulate mTORC1 activity. However, the contribution of REDD1 to the sepsis-induced change in muscle protein synthesis and degradation has not been determined. Sepsis was produced by cecal ligation and puncture in female REDD1−/− or wild-type (WT) mice, and end points were assessed 24 h later in gastrocnemius; time-matched, pair-fed controls of each genotype were included. Sepsis increased REDD1 protein 300% in WT mice, whereas REDD1 was absent in REDD1−/− muscle. Sepsis decreased protein synthesis and phosphorylation of downstream targets of mTORC1 (S6K1 Thr389, rpS6 Ser240/244, 4E-BP1 Ser65) in WT but not REDD1−/− mice. However, Akt and PRAS40 phosphorylation was suppressed in both sham and septic muscle from REDD1−/− mice despite unaltered PDK1, PP2A, or TSC2 expression. Sepsis increased autophagy as indicated by decreased ULK1 Ser757 phosphorylation and p62 abundance and increased LC3B-II/I in WT mice, whereas these changes were absent in septic REDD1−/− mice. Conversely, REDD1 deletion did not prevent the sepsis-induced decrease in IGF-I mRNA or the concomitant increase in IL-6, TNFα, MuRF1, and atrogin1 mRNA expression. Lastly, 5-day survival in a separate set of septic mice did not differ between WT and REDD1−/− mice. These data highlight the central role of REDD1 in regulating both protein synthesis and autophagy in skeletal muscle during sepsis.

scholarly journals Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling

2009 ◽  
Vol 106 (4) ◽  
pp. 1374-1384 ◽  
Author(s):  
Micah J. Drummond ◽  
Hans C. Dreyer ◽  
Christopher S. Fry ◽  
Erin L. Glynn ◽  
Blake B. Rasmussen
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Resistance Exercise ◽  
Human Skeletal Muscle ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Essential Amino Acids ◽  
Skeletal Muscle Protein ◽  
Mtorc1 Signaling

In this review we discuss current findings in the human skeletal muscle literature describing the acute influence of nutrients (leucine-enriched essential amino acids in particular) and resistance exercise on muscle protein synthesis and mammalian target of rapamycin complex 1 (mTORC1) signaling. We show that essential amino acids and an acute bout of resistance exercise independently stimulate human skeletal muscle protein synthesis. It also appears that ingestion of essential amino acids following resistance exercise leads to an even larger increase in the rate of muscle protein synthesis compared with the independent effects of nutrients or muscle contraction. Until recently the cellular mechanisms responsible for controlling the rate of muscle protein synthesis in humans were unknown. In this review, we highlight new studies in humans that have clearly shown the mTORC1 signaling pathway is playing an important regulatory role in controlling muscle protein synthesis in response to nutrients and/or muscle contraction. We propose that essential amino acid ingestion shortly following a bout of resistance exercise is beneficial in promoting skeletal muscle growth and may be useful in counteracting muscle wasting in a variety of conditions such as aging, cancer cachexia, physical inactivity, and perhaps during rehabilitation following trauma or surgery.

The order of concurrent endurance and resistance exercise modifies mTOR signaling and protein synthesis in rat skeletal muscle

2014 ◽  
Vol 306 (10) ◽  
pp. E1155-E1162 ◽  
Author(s):  
Riki Ogasawara ◽  
Koji Sato ◽  
Kenji Matsutani ◽  
Koichi Nakazato ◽  
Satoshi Fujita
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Resistance Exercise ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Concurrent Training ◽  
Control Group ◽  
Molecular Signaling ◽  
Muscle Adaptation ◽  
Mtorc1 Signaling

Concurrent training, a combination of endurance (EE) and resistance exercise (RE) performed in succession, may compromise the muscle hypertrophic adaptations induced by RE alone. However, little is known about the molecular signaling interactions underlying the changes in skeletal muscle adaptation during concurrent training. Here, we used an animal model to investigate whether EE before or after RE affects the molecular signaling associated with muscle protein synthesis, specifically the interaction between RE-induced mammalian target of rapamycin complex 1 (mTORC1) signaling and EE-induced AMP-activated protein kinase (AMPK) signaling. Male Sprague-Dawley rats were divided into five groups: an EE group (treadmill, 25 m/min, 60 min), an RE group (maximum isometric contraction via percutaneous electrical stimulation for 3 × 10 s, 5 sets), an EE before RE group, an EE after RE group, and a nonexercise control group. Phosphorylation of p70S6K, a marker of mTORC1 activity, was significantly increased 3 h after RE in both the EE before RE and EE after RE groups, but the increase was smaller in latter. Furthermore, protein synthesis was greatly increased 6 h after RE in the EE before RE group. Increases in the phosphorylation of AMPK and Raptor were observed only in the EE after RE group. Akt and mTOR phosphorylation were increased in both groups, with no between-group differences. Our results suggest that the last bout of exercise dictates the molecular responses and that mTORC1 signaling induced by any prior bout of RE may be downregulated by a subsequent bout of EE.

scholarly journals Phenotypic regulation of animal skeletal muscle protein metabolism

2019 ◽  
Vol 9 (4) ◽  
pp. 651-656 ◽  
Author(s):  
K. T. Erimbetov ◽  
O. V. Obvintseva ◽  
A. V. Fedorova ◽  
R. A. Zemlyanoy ◽  
A. G. Solovieva
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Signaling Pathways ◽  
Muscle Mass ◽  
Protein Metabolism ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mrna Translation ◽  
Mtorc1 Signaling ◽  
Muscle Protein Metabolism

This review highlights the current state of phenotypic mechanisms of regulation of muscle protein metabolism in animals. Since the skeletal muscle represents 40–50% of body mass in mammals it is a critical regulator of overall metabolism. Therefore, an understanding of the processes involved in the postnatal increase in muscle mass, with associated accumulation of protein, is fundamental. Throughout life, a delicate balance exists between protein synthesis and degradation that is essential for growth and normal health of humans and animals. Signaling pathways coordinate muscle protein balance. Anabolic and catabolic stimuli are integrated through the PKB/Akt-mTORC1 signaling to regulate mechanisms that control muscle protein synthesis and breakdown. At an early periods of intensive growth, muscle mass is stimulated by an increase in protein synthesis at the level of mRNA translation. Throughout the life, proteolytic processes including autophagy lysosomal system, ubiquitin proteasome pathway, calcium-dependent calpains and cysteine protease caspase enzyme cascade influence the growth of muscle mass. Several signal transmission networks direct and coordinate these processes along with quality control mechanisms to maintain protein homeostasis (proteostasis). Genetic factors, hormones, amino acids, phytoecdysteroids, and rhodanines affect the protein metabolism via signaling pathways, changing the ability and / or efficiency of muscle growth.

scholarly journals c-Myc overexpression increases ribosome biogenesis and protein synthesis independent of mTORC1 activation in mouse skeletal muscle

2021 ◽  
Author(s):  
Takahiro Mori ◽  
Satoru Ato ◽  
Jonas R. Knudsen ◽  
Carlos Henriquez-Olguin ◽  
Zhencheng Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Skeletal Muscles ◽  
Ribosome Biogenesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Mrna Translation ◽  
Adeno Associated Virus ◽  
Mtorc1 Signaling ◽  
Mtorc1 Activation

High-intensity muscle contractions (HiMC) are known to increase c-Myc expression which is known to stimulate ribosome biogenesis and protein synthesis in most cells. However, while c-Myc mRNA transcription and c-Myc mRNA translation have been shown to be upregulated following resistance exercise concomitantly with increased ribosome biogenesis, this has not been tested directly. We investigated the effect of adeno-associated virus (AAV)-mediated c-Myc overexpression, with or without fasting or percutaneous electrical stimulation-induced HiMC, on ribosome biogenesis and protein synthesis in adult mouse skeletal muscles. AAV-mediated overexpression of c-Myc in mouse skeletal muscles for 2 weeks increased the DNA polymerase subunit POL1 mRNA, 45S-pre-rRNA, total RNA, and muscle protein synthesis without altering mechanistic target of rapamycin complex 1 (mTORC1) signaling under both ad libitum and fasted conditions. RNA-seq analyses revealed that c-Myc overexpression mainly regulated ribosome biogenesis-related biological processes. The protein synthesis response to c-Myc overexpression mirrored the response with HiMC. No additional effect of combining c-Myc overexpression and HiMC was observed. Our results suggest that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1. Therefore, the HiMC-induced increase in c-Myc may contribute to ribosome biogenesis and increased protein synthesis following HiMC.

scholarly journals Blocking of myostatin and activins increase muscle protein synthesis and mTORC1 signaling but decreases capillary density

2012 ◽  
Vol 26 (S1) ◽  
Author(s):  
Juha J Hulmi ◽  
Bernardo M Oliveira ◽  
Mika Silvennoinen ◽  
Hongqiang Ma ◽  
Philippe Pierre ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Capillary Density ◽  
Mtorc1 Signaling
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