scholarly journals Mechanisms of IGF-1-Mediated Regulation of Skeletal Muscle Hypertrophy and Atrophy

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 1970 ◽  
Author(s):  
Tadashi Yoshida ◽  
Patrice Delafontaine
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Growth Factor ◽  
Muscle Atrophy ◽  
Muscle Regeneration ◽  
Muscle Hypertrophy ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Regeneration ◽  
Skeletal Muscle Atrophy

Insulin-like growth factor-1 (IGF-1) is a key growth factor that regulates both anabolic and catabolic pathways in skeletal muscle. IGF-1 increases skeletal muscle protein synthesis via PI3K/Akt/mTOR and PI3K/Akt/GSK3β pathways. PI3K/Akt can also inhibit FoxOs and suppress transcription of E3 ubiquitin ligases that regulate ubiquitin proteasome system (UPS)-mediated protein degradation. Autophagy is likely inhibited by IGF-1 via mTOR and FoxO signaling, although the contribution of autophagy regulation in IGF-1-mediated inhibition of skeletal muscle atrophy remains to be determined. Evidence has suggested that IGF-1/Akt can inhibit muscle atrophy-inducing cytokine and myostatin signaling via inhibition of the NF-κΒ and Smad pathways, respectively. Several miRNAs have been found to regulate IGF-1 signaling in skeletal muscle, and these miRs are likely regulated in different pathological conditions and contribute to the development of muscle atrophy. IGF-1 also potentiates skeletal muscle regeneration via activation of skeletal muscle stem (satellite) cells, which may contribute to muscle hypertrophy and/or inhibit atrophy. Importantly, IGF-1 levels and IGF-1R downstream signaling are suppressed in many chronic disease conditions and likely result in muscle atrophy via the combined effects of altered protein synthesis, UPS activity, autophagy, and muscle regeneration.

scholarly journals Z-ajoene from Crushed Garlic Alleviates Cancer-Induced Skeletal Muscle Atrophy

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2724 ◽  
Author(s):  
Hyejin Lee ◽  
Ji-Won Heo ◽  
A-Reum Kim ◽  
Minson Kweon ◽  
Sorim Nam ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Atrophy ◽  
Cancer Cachexia ◽  
Inflammatory Responses ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Janus Kinase ◽  
Skeletal Muscle Atrophy ◽  
E3 Ligases

Skeletal muscle atrophy is one of the major symptoms of cancer cachexia. Garlic (Allium sativum), one of the world’s most commonly used and versatile herbs, has been employed for the prevention and treatment of diverse diseases for centuries. In the present study, we found that ajoene, a sulfur compound found in crushed garlic, exhibits protective effects against muscle atrophy. Using CT26 tumor-bearing BALB/c mice, we demonstrate in vivo that ajoene extract alleviated muscle degradation by decreasing not only myokines secretion but also janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3) and SMADs/forkhead box (FoxO) signaling pathways, thereby suppressing muscle-specific E3 ligases. In mouse skeletal myoblasts, Z-ajoene enhanced myogenesis as evidenced by increased expression of myogenic markers via p38 mitogen-activated protein kinase (MAPK) activation. In mature myotubes, Z-ajoene protected against muscle protein degradation induced by conditioned media from CT26 colon carcinoma cells, by suppressing expression of muscle specific E3 ligases and nuclear transcription factor kappa B (NF-κB) phosphorylation which contribute to muscle atrophy. Moreover, Z-ajoene treatment improved myofiber formation via stimulation of muscle protein synthesis. These findings suggest that ajoene extract and Z-ajoene can attenuate skeletal muscle atrophy induced by cancer cachexia through suppressing inflammatory responses and the muscle wasting as well as by promoting muscle protein synthesis.

scholarly journals Short-Term Oxandrolone Administration Stimulates Net Muscle Protein Synthesis in Young Men1

1999 ◽  
Vol 84 (8) ◽  
pp. 2705-2711 ◽  
Author(s):  
Melinda Sheffield-Moore ◽  
Randall J. Urban ◽  
Steven E. Wolf ◽  
J. Jiang ◽  
Don H. Catlin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amino Acids ◽  
Protein Synthesis ◽  
Growth Factor ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Rt Pcr ◽  
Short Term ◽  
Healthy Men ◽  
Factor I

Short term administration of testosterone stimulates net protein synthesis in healthy men. We investigated whether oxandrolone[ Oxandrin (OX)], a synthetic analog of testosterone, would improve net muscle protein synthesis and transport of amino acids across the leg. Six healthy men [22 ± 1 (±se) yr] were studied in the postabsorptive state before and after 5 days of oral OX (15 mg/day). Muscle protein synthesis and breakdown were determined by a three-compartment model using stable isotopic data obtained from femoral arterio-venous sampling and muscle biopsy. The precursor-product method was used to determine muscle protein fractional synthetic rates. Fractional breakdown rates were also directly calculated. Total messenger ribonucleic acid (mRNA) concentrations of skeletal muscle insulin-like growth factor I and androgen receptor (AR) were determined using RT-PCR. Model-derived muscle protein synthesis increased from 53.5 ± 3 to 68.3 ± 5 (mean ± se) nmol/min·100 mL/leg (P < 0.05), whereas protein breakdown was unchanged. Inward transport of amino acids remained unchanged with OX, whereas outward transport decreased (P < 0.05). The fractional synthetic rate increased 44% (P < 0.05) after OX administration, with no change in fractional breakdown rate. Therefore, the net balance between synthesis and breakdown became more positive with both methodologies (P < 0.05) and was not different from zero. Further, RT-PCR showed that OX administration significantly increased mRNA concentrations of skeletal muscle AR without changing insulin-like growth factor I mRNA concentrations. We conclude that short term OX administration stimulated an increase in skeletal muscle protein synthesis and improved intracellular reutilization of amino acids. The mechanism for this stimulation may be related to an OX-induced increase in AR expression in skeletal muscle.

scholarly journals Exercise-Induced Muscle Damage and Hypertrophy: A Closer Look Reveals the Jury is Still Out

2018 ◽  
Author(s):  
Brad Jon Schoenfeld ◽  
Bret Contreras
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Resistance Training ◽  
Muscle Damage ◽  
Muscle Hypertrophy ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Skeletal Muscle Hypertrophy ◽  
Exercise Induced

This letter is a response to the paper by Damas et al (2017) titled, “The development of skeletal muscle hypertrophy through resistance training: the role of muscle damage and muscle protein synthesis,” which, in part, endeavored to review the role of exercise-induced muscle damage on muscle hypertrophy. We feel there are a number of issues in interpretation of research and extrapolation that preclude drawing the inference expressed in the paper that muscle damage neither explains nor potentiates increases in muscle hypertrophy. The intent of our letter is not to suggest that a causal role exists between hypertrophy and microinjury. Rather, we hope to provide balance to the evidence presented and offer the opinion that the jury is still very much out as to providing answers on the topic.

Differential effect of sepsis on ability of leucine and IGF-I to stimulate muscle translation initiation

2004 ◽  
Vol 287 (4) ◽  
pp. E721-E730 ◽  
Author(s):  
Charles H. Lang ◽  
Robert A. Frost
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Growth Factor ◽  
Translation Initiation ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Growth Factor I ◽  
Signaling Components

Polymicrobial sepsis impairs skeletal muscle protein synthesis, which results from impairment in translation initiation under basal conditions. The purpose of the present study was to test the hypothesis that sepsis also impairs the anabolic response to amino acids, specifically leucine (Leu). Sepsis was induced by cecal ligation and puncture, and 24 h later, Leu or saline (Sal) was orally administered to septic and time-matched nonseptic rats. The gastrocnemius was removed 20 min later for assessment of protein synthesis and signaling components important in peptide-chain initiation. Oral Leu increased muscle protein synthesis in nonseptic rats. Leu was unable to increase protein synthesis in muscle from septic rats, and synthetic rates remained below those observed in nonseptic + Sal rats. In nonseptic + Leu rats, phosphorylation of eukaryotic initiation factor (eIF)4E-binding protein 1 (4E-BP1) in muscle was markedly increased compared with values from time-matched Sal-treated nonseptic rats. This change was associated with redistribution of eIF4E from the inactive eIF4E·4E-BP1 to the active eIF4E·eIF4G complex. In septic rats, Leu-induced phosphorylation of 4E-BP1 and changes in eIF4E distribution were completely abrogated. Sepsis also antagonized the Leu-induced increase in phosphorylation of S6 kinase 1 and ribosomal protein S6. Sepsis attenuated Leu-induced phosphorylation of mammalian target of rapamycin and eIF4G. The ability of sepsis to inhibit anabolic effects of Leu could not be attributed to differences in plasma concentrations of insulin, insulin-like growth factor I, or Leu between groups. In contrast, the ability of exogenous insulin-like growth factor I to stimulate the same signaling components pertaining to translation initiation was not impaired by sepsis. Hence, sepsis produces a relatively specific Leu resistance in skeletal muscle that impairs the ability of this amino acid to stimulate translation initiation and protein synthesis.

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 Thyroid Hormone Action in Muscle Atrophy

Metabolites ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 730
Author(s):  
Maria Angela De Stefano ◽  
Raffaele Ambrosio ◽  
Tommaso Porcelli ◽  
Gianfranco Orlandino ◽  
Domenico Salvatore ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Thyroid Hormone ◽  
Muscle Atrophy ◽  
Molecular Mechanisms ◽  
Muscle Protein ◽  
Active Form ◽  
Skeletal Muscle Atrophy ◽  
Target Tissue ◽  
Muscle Mass Loss

Skeletal muscle atrophy is a condition associated with various physiological and pathophysiological conditions, such as denervation, cachexia, and fasting. It is characterized by an altered protein turnover in which the rate of protein degradation exceeds the rate of protein synthesis, leading to substantial muscle mass loss and weakness. Muscle protein breakdown reflects the activation of multiple proteolytic mechanisms, including lysosomal degradation, apoptosis, and ubiquitin–proteasome. Thyroid hormone (TH) plays a key role in these conditions. Indeed, skeletal muscle is among the principal TH target tissue, where TH regulates proliferation, metabolism, differentiation, homeostasis, and growth. In physiological conditions, TH stimulates both protein synthesis and degradation, and an alteration in TH levels is often responsible for a specific myopathy. Intracellular TH concentrations are modulated in skeletal muscle by a family of enzymes named deiodinases; in particular, in muscle, deiodinases type 2 (D2) and type 3 (D3) are both present. D2 activates the prohormone T4 into the active form triiodothyronine (T3), whereas D3 inactivates both T4 and T3 by the removal of an inner ring iodine. Here we will review the present knowledge of TH action in skeletal muscle atrophy, in particular, on the molecular mechanisms presiding over the control of intracellular T3 concentration in wasting muscle conditions. Finally, we will discuss the possibility of exploiting the modulation of deiodinases as a possible therapeutic approach to treat muscle atrophy.

scholarly journals Notch Inhibition via GSI Treatment Elevates Protein Synthesis in C2C12 Myotubes

Biology ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 115
Author(s):  
Joshua R. Huot ◽  
Joseph S. Marino ◽  
Michael J. Turner ◽  
Susan T. Arthur
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Notch Signaling ◽  
Muscle Protein ◽  
Muscle Protein Synthesis ◽  
C2c12 Cells ◽  
Skeletal Muscle Regeneration ◽  
C2c12 Myotubes ◽  
Myonuclear Domain ◽  
Myotube Hypertrophy

The role of Notch signaling is widely studied in skeletal muscle regeneration but little is known about its influences on muscle protein synthesis (MPS). The purpose of this study was to investigate whether Notch signaling is involved in the regulation of MPS. C2C12 cells were treated with a γ-secretase inhibitor (GSI), to determine the effect of reduced Notch signaling on MPS and anabolic signaling markers. GSI treatment increased myotube hypertrophy by increasing myonuclear accretion (nuclei/myotube: p = 0.01) and myonuclear domain (myotube area per fusing nuclei: p < 0.001) in differentiating C2C12 cells. GSI treatment also elevated myotube hypertrophy in differentiated C2C12s (area/myotube; p = 0.01). In concert, GSI treatment augmented pmTOR Ser2448 (p = 0.01) and protein synthesis (using SUnSET method) in myotubes (p < 0.001). Examining protein expression upstream of mTOR revealed reductions in PTEN (p = 0.04), with subsequent elevations in pAKT Thr308 (p < 0.001) and pAKT Ser473 (p = 0.05). These findings reveal that GSI treatment elevates myotube hypertrophy through both augmentation of fusion and MPS. This study sheds light on the potential multifaceted roles of Notch within skeletal muscle. Furthermore, we have demonstrated that Notch may modulate the PTEN/AKT/mTOR pathway.

scholarly journals MBNL1 reverses the proliferation defect of skeletal muscle satellite cells in myotonic dystrophy type 1 by inhibiting autophagy via the mTOR pathway

2020 ◽  
Vol 11 (7) ◽  
Author(s):  
Kai-Yi Song ◽  
Xiu-Ming Guo ◽  
Hui-Qi Wang ◽  
Lei Zhang ◽  
Si-Yuan Huang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Myotonic Dystrophy ◽  
Muscle Atrophy ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Skeletal Muscle Regeneration ◽  
Skeletal Muscle Atrophy ◽  
Myotonic Dystrophy Type 1 ◽  
Myotonic Dystrophy Type

Abstract Skeletal muscle atrophy is one of the clinical symptoms of myotonic dystrophy type 1 (DM1). A decline in skeletal muscle regeneration is an important contributor to muscle atrophy. Skeletal muscle satellite cells (SSCs) drive skeletal muscle regeneration. Increased autophagy can reduce the proliferative capacity of SSCs, which plays an important role in the early regeneration of damaged skeletal muscle in DM1. Discovering new ways to restore SSC proliferation may aid in the identification of new therapeutic targets for the treatment of skeletal muscle atrophy in DM1. In the pathogenesis of DM1, muscleblind-like 1 (MBNL1) protein is generally considered to form nuclear RNA foci and disturb the RNA-splicing function. However, the role of MBNL1 in SSC proliferation in DM1 has not been reported. In this study, we obtained SSCs differentiated from normal DM1-04-induced pluripotent stem cells (iPSCs), DM1-03 iPSCs, and DM1-13-3 iPSCs edited by transcription activator-like (TAL) effector nucleases (TALENs) targeting CTG repeats, and primary SSCs to study the pathogenesis of DM1. DM1 SSC lines and primary SSCs showed decreased MBNL1 expression and elevated autophagy levels. However, DM1 SSCs edited by TALENs showed increased cytoplasmic distribution of MBNL1, reduced levels of autophagy, increased levels of phosphorylated mammalian target of rapamycin (mTOR), and improved proliferation rates. In addition, we confirmed that after MBNL1 overexpression, the proliferative capability of DM1 SSCs and the level of phosphorylated mTOR were enhanced, while the autophagy levels were decreased. Our data also demonstrated that the proliferative capability of DM1 SSCs was enhanced after autophagy was inhibited by overexpressing mTOR. Finally, treatment with rapamycin (an mTOR inhibitor) was shown to abolish the increased proliferation capability of DM1 SSCs due to MBNL1 overexpression. Taken together, these data suggest that MBNL1 reverses the proliferation defect of SSCs in DM1 by inhibiting autophagy via the mTOR pathway.

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