scholarly journals The m6A methyltransferase METTL3 regulates muscle maintenance and growth in mice

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Jennifer M. Petrosino ◽  
Scott A. Hinger ◽  
Volha A. Golubeva ◽  
Juan M. Barajas ◽  
Lisa E. Dorn ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Growth ◽  
Muscle Size ◽  
Hypertrophic Response ◽  
Hypertrophic Growth ◽  
Genome Wide ◽  
Muscle Proteome ◽  
Exogenous Delivery ◽  
Muscle Homeostasis

AbstractSkeletal muscle serves fundamental roles in organismal health. Gene expression fluctuations are critical for muscle homeostasis and the response to environmental insults. Yet, little is known about post-transcriptional mechanisms regulating such fluctuations while impacting muscle proteome. Here we report genome-wide analysis of mRNA methyladenosine (m6A) dynamics of skeletal muscle hypertrophic growth following overload-induced stress. We show that increases in METTL3 (the m6A enzyme), and concomitantly m6A, control skeletal muscle size during hypertrophy; exogenous delivery of METTL3 induces skeletal muscle growth, even without external triggers. We also show that METTL3 represses activin type 2 A receptors (ACVR2A) synthesis, blunting activation of anti-hypertrophic signaling. Notably, myofiber-specific conditional genetic deletion of METTL3 caused spontaneous muscle wasting over time and abrogated overload-induced hypertrophy; a phenotype reverted by co-administration of a myostatin inhibitor. These studies identify a previously unrecognized post-transcriptional mechanism promoting the hypertrophic response of skeletal muscle via control of myostatin signaling.

scholarly journals Making Mice Mighty: recent advances in translational models of load-induced muscle hypertrophy

2020 ◽  
Vol 129 (3) ◽  
pp. 516-521 ◽  
Author(s):  
Kevin A. Murach ◽  
John J. McCarthy ◽  
Charlotte A. Peterson ◽  
Cory M. Dungan
Keyword(s):  
Skeletal Muscle ◽  
Muscle Hypertrophy ◽  
Muscle Growth ◽  
Therapeutic Interventions ◽  
Loss Of Function ◽  
Hypertrophic Response ◽  
Advantages And Disadvantages ◽  
Muscle Loading ◽  
Specific Factors

The ability to genetically manipulate mice allows for gain- and loss-of-function in vivo, making them an ideal model for elucidating mechanisms of skeletal muscle mass regulation. Combining genetic models with mechanical muscle loading enables identification of specific factors involved in the hypertrophic response as well as the ability to test the requirement of those factors for adaptation, thereby informing performance and therapeutic interventions. Until recently, approaches for inducing mechanically mediated muscle hypertrophy (i.e., resistance-training analogs) have been limited and considered “nontranslatable” to humans. This mini-review outlines recent translational advances in loading-mediated strategies for inducing muscle hypertrophy in mice, and highlights the advantages and disadvantages of each method. The skeletal muscle field is poised for new breakthroughs in understanding mechanisms regulating load-induced muscle growth given the numerous murine tools that have very recently been described.

scholarly journals Skeletal-muscle growth and protein turnover

1975 ◽  
Vol 150 (2) ◽  
pp. 235-243 ◽  
Author(s):  
D J Millward ◽  
P J Garlick ◽  
R J C Stewart ◽  
D O Nnanyelugo ◽  
J C Waterlow
Keyword(s):  
Skeletal Muscle ◽  
Growth Rate ◽  
Protein Synthesis ◽  
Muscle Protein ◽  
Muscle Growth ◽  
Muscle Size ◽  
Synthesis Rate ◽  
Protein Breakdown ◽  
Breakdown Rate ◽  
Breakdown Rates

Because of turnover, protein synthesis and breakdown can each be involved in the regulation of the growth of tissue protein. To investigate the regulation of skeletal-muscle-protein growth we measured rates of protein synthesis and breakdown in growing rats during development on a good diet, during development on a marginally low-protein diet and during rehabilitation on a good diet after a period of severe protein deficiency. Rates of protein synthesis were measured in vivo with a constant intravenous infusion of [14C]tyrosine. The growth rate of muscle protein was measured and the rate of breakdown calculated as breakdown rate=synthesis rate-growth rate. These measurements showed that during development on a good diet there was a fall with age in the rate of protein synthesis resulting from a fall in capacity (RNA concentration) and activity (synthesis rate per unit of RNA). There was a fall with age in the breakdown rate so that the rate was highest in the weaning rats, with a half-life of 3 days. There was a direct correlation between the fractional growth and breakdown rates. During rehabilitation on the good diet, rapid growth was also accompanied by high rates of protein breakdown. During growth on the inadequate diet protein synthesis rates were lesss than in controls, but growth occurred because of decreased rates of protein breakdown. This compression was not complete, however, since ultimate muscle size was only one-half that of controls. It is suggested that increased rates of protein breakdown are a necessary accompaniment to muscle growth and may result from the way in which myofibrils proliferate.

Genome-wide meta-analysis associates GPSM1 with type 2 diabetes, a plausible gene involved in skeletal muscle function

2020 ◽  
Vol 65 (4) ◽  
pp. 411-420
Author(s):  
Qiuju Ding ◽  
Amelia Li Min Tan ◽  
E. J. Parra ◽  
Miguel Cruz ◽  
Xueling Sim ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Muscle Function ◽  
Meta Analysis ◽  
Skeletal Muscle Function ◽  
Genome Wide

scholarly journals Crosstalk between Mitochondrial Ca2+ Uptake and Autophagy in Skeletal Muscle

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Gaia Gherardi ◽  
Giulia Di Marco ◽  
Rosario Rizzuto ◽  
Cristina Mammucari
Keyword(s):  
Skeletal Muscle ◽  
Energy Production ◽  
Nutrient Utilization ◽  
Muscle Size ◽  
Autophagic Flux ◽  
Autophagy Flux ◽  
Autophagy Gene ◽  
Selective Channel ◽  
Muscle Homeostasis ◽  
Specific Deletion

Autophagy is responsible for the maintenance of skeletal muscle homeostasis, thanks to the removal of aberrant and dysfunctional macromolecules and organelles. During fasting, increased autophagy ensures the maintenance of the amino acid pool required for energy production. The activity of the mitochondrial Ca2+ uniporter (MCU), the highly selective channel responsible for mitochondrial Ca2+ uptake, controls skeletal muscle size, force, and nutrient utilization. Thus, both autophagy and mitochondrial Ca2+ accumulation play a pivotal role to maintain muscle homeostasis and to sustain muscle function. Here, we address whether, in skeletal muscle, mitochondrial Ca2+ uptake and autophagy are mutually related. Muscle-restricted MCU silencing partially inhibits the autophagy flux. Moreover, skeletal muscle-specific deletion of the essential autophagy gene Atg7, known to cause the accumulation of dysfunctional mitochondria, drastically reduces mitochondrial Ca2+ accumulation. Thus, a vicious cycle takes place, in which reduced MCU activity hampers the autophagic flux, and loss of autophagy further impairs mitochondrial Ca2+ signaling.

scholarly journals Transthyretin Maintains Muscle Homeostasis through the Novel Shuttle Pathway of Thyroid Hormones during Myoblast Differentiation

Cells ◽  
2019 ◽  
Vol 8 (12) ◽  
pp. 1565 ◽  
Author(s):  
Eun Ju Lee ◽  
Sibhghatulla Shaikh ◽  
Dukhwan Choi ◽  
Khurshid Ahmad ◽  
Mohammad Hassan Baig ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormones ◽  
Muscle Growth ◽  
Vital Role ◽  
Myoblast Differentiation ◽  
Mouse Muscle ◽  
Total Body Mass ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
Muscle Homeostasis

Skeletal muscle, the largest part of the total body mass, influences energy and protein metabolism as well as maintaining homeostasis. Herein, we demonstrate that during murine muscle satellite cell and myoblast differentiation, transthyretin (TTR) can exocytose via exosomes and enter cells as TTR- thyroxine (T4) complex, which consecutively induces the intracellular triiodothyronine (T3) level, followed by T3 secretion out of the cell through the exosomes. The decrease in T3 with the TTR level in 26-week-old mouse muscle, compared to that in 16-week-old muscle, suggests an association of TTR with old muscle. Subsequent studies, including microarray analysis, demonstrated that T3-regulated genes, such as FNDC5 (Fibronectin type III domain containing 5, irisin) and RXRγ (Retinoid X receptor gamma), are influenced by TTR knockdown, implying that thyroid hormones and TTR coordinate with each other with respect to muscle growth and development. These results suggest that, in addition to utilizing T4, skeletal muscle also distributes generated T3 to other tissues and has a vital role in sensing the intracellular T4 level. Furthermore, the results of TTR function with T4 in differentiation will be highly useful in the strategic development of novel therapeutics related to muscle homeostasis and regeneration.

scholarly journals Srf controls satellite cell fusion through the maintenance of actin architecture

2017 ◽  
Vol 217 (2) ◽  
pp. 685-700 ◽  
Author(s):  
Voahangy Randrianarison-Huetz ◽  
Aikaterini Papaefthymiou ◽  
Gaëlle Herledan ◽  
Chiara Noviello ◽  
Ulduz Faradova ◽  
...  
Keyword(s):  
Actin Cytoskeleton ◽  
Serum Response Factor ◽  
Control Cell ◽  
Muscle Growth ◽  
Muscle Stem Cells ◽  
Hypertrophic Growth ◽  
Proliferation And Differentiation ◽  
Muscle Homeostasis

Satellite cells (SCs) are adult muscle stem cells that are mobilized when muscle homeostasis is perturbed. Here, we show that serum response factor (Srf) is needed for optimal SC-mediated hypertrophic growth. We identified Srf as a master regulator of SC fusion required in both fusion partners, whereas it was dispensable for SC proliferation and differentiation. We show that SC-specific Srf deletion leads to impaired actin cytoskeleton and report the existence of finger-like actin–based protrusions at fusion sites in vertebrates that were notoriously absent in fusion-defective myoblasts lacking Srf. Restoration of a polymerized actin network by overexpression of an α-actin isoform in Srf mutant SCs rescued their fusion with a control cell in vitro and in vivo and reestablished overload-induced muscle growth. These findings demonstrate the importance of Srf in controlling the organization of actin cytoskeleton and actin-based protrusions for myoblast fusion in mammals and its requirement to achieve efficient hypertrophic myofiber growth.

GH regulation of the Type 2 IGF receptor in regenerating skeletal muscle of rats

1996 ◽  
Vol 149 (1) ◽  
pp. 81-91 ◽  
Author(s):  
S P Kirk ◽  
M A Whittle ◽  
J M Oldham ◽  
P M Dobbie ◽  
J J Bass
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Muscle Growth ◽  
Biceps Femoris ◽  
Tissue Type ◽  
Muscle Tissues ◽  
Igf Receptor ◽  
The Right ◽  
First Time

Abstract GH enhances skeletal muscle growth, and IGF-II peptide is highly expressed during regeneration. We have therefore investigated the effect of GH administration on IGF-II binding and expression in regenerating rat skeletal muscle using the techniques of receptor autoradiography and in situ hybridisation. Notexin, a myotoxin, was injected into the right M. biceps femoris (day 0), causing affected fibres to undergo necrosis followed by rapid regeneration. Animals were administered either GH (200 μg/100 g body weight) or saline vehicle daily. Contralateral muscles were used as regeneration controls. GH administration during regeneration resulted in significant increases in body weight, and damaged and undamaged muscle weights (P<0·001). IGF-II expression, which was examined in regenerating fibres, survivor fibres and undamaged fibres, varied according to tissue type (P< 0·001). Specifically, IGF-II expression in regenerating fibres was elevated relative to control and survivor fibres after day 3 (P<0·05), with a peak on day 9 (P<0·001). GH did not affect IGF-II message levels. 125I-IGF-II binding in regenerating muscle was examined in the same fibre types as well as in connective tissue. 125I-IGF-II binding in regenerating fibres was higher (P<0·001) than in other tissue types on day 5. GH administration increased 125I-IGF-II binding in all damaged muscle tissues on day 5 (P<0·001, regenerating fibres; P<0·01, others). We believe that this shows for the first time an effect of GH on the Type 2 IGF receptor in regenerating skeletal muscle. Journal of Endocrinology (1996) 149, 81–91

scholarly journals MicroRNA-193b impairs muscle growth in mouse models of type 2 diabetes by targeting the PDK1/Akt signalling pathway

Diabetologia ◽  
2021 ◽  
Author(s):  
Shu Yang ◽  
Guangyan Yang ◽  
Han Wu ◽  
Lin Kang ◽  
Jiaqing Xiang ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Muscle Mass ◽  
Fasting Blood Glucose ◽  
Muscle Growth ◽  
Mammalian Target Of Rapamycin ◽  
Skeletal Muscle Atrophy ◽  
Muscle Loss ◽  
Functional Studies

Abstract Aims/hypothesis Type 2 diabetes is associated with a reduction in skeletal muscle mass; however, how the progression of sarcopenia is induced and regulated remains largely unknown. We aimed to find out whether a specific microRNA (miR) may contribute to skeletal muscle atrophy in type 2 diabetes. Methods Adeno-associated virus (AAV)-mediated skeletal muscle miR-193b overexpression in C57BLKS/J mice, and skeletal muscle miR-193b deficiency in db/db mice were used to explore the function of miR-193b in muscle loss. In C57BL/6 J mice, tibialis anterior-specific deletion of 3-phosphoinositide-dependent protein kinase-1 (PDK1), mediated by in situ AAV injection, was used to confirm whether miR-193b regulates muscle growth through PDK1. Serum miR-193b levels were also analysed in healthy individuals (n = 20) and those with type 2 diabetes (n = 20), and correlations of miR-193b levels with HbA1c, fasting blood glucose (FBG), body composition, triacylglycerols and C-peptide were assessed. Results In this study, we found that serum miR-193b levels increased in individuals with type 2 diabetes and negatively correlated with muscle mass in these participants. Functional studies further showed that AAV-mediated overexpression of miR-193b induced muscle loss and dysfunction in healthy mice. In contrast, suppression of miR-193b attenuated muscle loss and dysfunction in db/db mice. Mechanistic analysis revealed that miR-193b could target Pdk1 expression to inactivate the Akt/mammalian target of rapamycin (mTOR)/p70S6 kinase (S6K) pathway, thereby inhibiting protein synthesis. Therefore, knockdown of PDK1 in healthy mice blocked miR-193b-induced inactivation of the Akt/mTOR/S6K pathway and impairment of muscle growth. Conclusions/interpretation Our results identified a previously unrecognised role of miR-193b in muscle function and mass that could be a potential therapeutic target for treating sarcopenia. Graphical abstract

scholarly journals Acute effects of insulin on skeletal muscle growth and differentiation genes in men with type 2 diabetes

2019 ◽  
Vol 181 (6) ◽  
pp. K55-K59 ◽  
Author(s):  
Sandeep Dhindsa ◽  
Husam Ghanim ◽  
Kelly Green ◽  
Sanaa Abuaysheh ◽  
Manav Batra ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Hypogonadotropic Hypogonadism ◽  
Muscle Growth ◽  
Quadriceps Muscle ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Potent Effect ◽  
Myogenic Regulatory Factor

Aims Insulin has anabolic effects on skeletal muscle. However, there is limited understanding of the molecular mechanisms underlying this effect in humans. We evaluated whether the skeletal muscle expression of satellite cell activator fibroblast growth factor 2 (FGF2) and muscle growth and differentiation factors are modulated acutely by insulin during euglycemic–hyperinsulinemic clamp (EHC). Design and methods This is a secondary investigation and analysis of samples obtained from a previously completed trial investigating the effect of testosterone replacement in males with hypogonadotropic hypogonadism and type 2 diabetes. Twenty men with type 2 diabetes underwent quadriceps muscle biopsies before and after 4 h of EHC. Results The infusion of insulin during EHC raised the expression of myogenic growth factors, myogenin (by 72 ± 20%) and myogenin differentiation protein (MyoD; by 81 ± 22%). Insulin reduced the expression of muscle hypertrophy suppressor, myogenic regulatory factor 4 (MRF4) by 34 ± 14%. In addition, there was an increase in expression of FGF receptor 2, but not FGF2, following EHC. The expression of myostatin did not change. Conclusions Insulin has an acute potent effect on expression of genes that can stimulate muscle differentiation and growth.

The effect of the anabolic agent, clenbuterol, on overloaded rat skeletal muscle

1987 ◽  
Vol 7 (2) ◽  
pp. 143-149 ◽  
Author(s):  
C. A. Maltin ◽  
M. I. Delday ◽  
S. M. Hay ◽  
F. G. Smith ◽  
G. E. Lobley ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Drug Treatment ◽  
Growth Response ◽  
Muscle Growth ◽  
Young Male ◽  
Male Rats ◽  
Rat Skeletal Muscle ◽  
Anabolic Agent ◽  
Hypertrophic Growth ◽  
Fibre Size

The dietary administration of clenbuterol to young male rats has been shown to produce a muscle specific hypertrophic growth response. This paper demonstrates that the combined effect of drug treatment and hypertrophic stimulus induced by tenotomy produced an additive effect on muscle growth. This effect was demonstrated in terms of both muscle composition (protein and RNA) and fibre size.

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