The Regulation of Polyamine Pathway Proteins in Models of Skeletal Muscle Hypertrophy and Atrophy - a potential role for mTORC1

Polyamines have been shown to be absolutely required for protein synthesis and cell growth. The serine/threonine kinase, the mechanistic target of rapamycin complex 1 (mTORC1), also plays a fundamental role in the regulation of protein turnover and cell size, including in skeletal muscle, where mTORC1 is sufficient to increase protein synthesis and muscle fiber size, and is necessary for mechanical overload-induced muscle hypertrophy. Recent evidence suggests that mTORC1 may regulate the polyamine metabolic pathway; however, there is currently no evidence in skeletal muscle. This study examined changes in polyamine pathway proteins during muscle hypertrophy induced by mechanical overload (7 d), with and without the mTORC1 inhibitor, rapamycin, and during muscle atrophy induced by food deprivation (48 h) and denervation (7 d) in mice. Mechanical overload induced an increase in mTORC1 signalling, protein synthesis and muscle mass, and these were associated with rapamycin-sensitive increases in adenosylmethione decarboxylase 1 (Amd1), spermidine synthase (SpdSyn) and c-Myc. Food deprivation decreased mTORC1 signalling, protein synthesis and muscle mass, accompanied by a decrease in spermidine/spermine acetyltransferase 1 (Sat1). Denervation, resulted increased mTORC1 signalling and protein synthesis, and decreased muscle mass, which was associated with an increase in SpdSyn, spermine synthase (SpmSyn) and c-Myc. Combined, these data show that polyamine pathway enzymes are differentially regulated in models of altered mechanical and metabolic stress, and that Amd1 and SpdSyn are, in part, regulated in a mTORC1-dependent manner. Furthermore, these data suggest that polyamines may play a role in the adaptive response to stressors in skeletal muscle.

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Akt1 deficiency diminishes skeletal muscle hypertrophy by reducing satellite cell proliferation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00336.2017 ◽

2018 ◽

Vol 314 (5) ◽

pp. R741-R751 ◽

Cited By ~ 11

Author(s):

Nobuki Moriya ◽

Mitsunori Miyazaki

Keyword(s):

Skeletal Muscle ◽

Cell Proliferation ◽

Protein Synthesis ◽

Satellite Cell ◽

Muscle Mass ◽

Satellite Cells ◽

Muscle Hypertrophy ◽

Mtor Signaling ◽

Skeletal Muscle Hypertrophy ◽

Satellite Cell Proliferation

Skeletal muscle mass is determined by the net dynamic balance between protein synthesis and degradation. Although the Akt/mechanistic target of rapamycin (mTOR)-dependent pathway plays an important role in promoting protein synthesis and subsequent skeletal muscle hypertrophy, the precise molecular regulation of mTOR activity by the upstream protein kinase Akt is largely unknown. In addition, the activation of satellite cells has been indicated as a key regulator of muscle mass. However, the requirement of satellite cells for load-induced skeletal muscle hypertrophy is still under intense debate. In this study, female germline Akt1 knockout (KO) mice were used to examine whether Akt1 deficiency attenuates load-induced skeletal muscle hypertrophy through suppressing mTOR-dependent signaling and satellite cell proliferation. Akt1 KO mice showed a blunted hypertrophic response of skeletal muscle, with a diminished rate of satellite cell proliferation following mechanical overload. In contrast, Akt1 deficiency did not affect the load-induced activation of mTOR signaling and the subsequent enhanced rate of protein synthesis in skeletal muscle. These observations suggest that the load-induced activation of mTOR signaling occurs independently of Akt1 regulation and that Akt1 plays a critical role in regulating satellite cell proliferation during load-induced muscle hypertrophy.

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Role of mTORC1 in mechanically induced increases in translation and skeletal muscle mass

Journal of Applied Physiology ◽

10.1152/japplphysiol.01011.2018 ◽

2019 ◽

Vol 127 (2) ◽

pp. 581-590 ◽

Cited By ~ 22

Author(s):

Craig A. Goodman

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Mrna Translation ◽

Current Evidence ◽

Mechanical Stimuli ◽

Serine Threonine Kinase ◽

Mtor Complex 1

Skeletal muscle mass is, in part, regulated by the rate of mRNA translation (i.e., protein synthesis). The conserved serine/threonine kinase, mTOR (the mammalian/mechanistic target of rapamycin), found in the multiprotein complex, mTOR complex 1 (mTORC1), is a major positive regulator of protein synthesis. The purpose of this review is to describe some of the critical steps in translation initiation, mTORC1 and its potential direct and indirect roles in regulating translation, and evidence that mTORC1 regulates protein synthesis and muscle mass, with a particular focus on basal conditions and the response to mechanical stimuli. Current evidence suggests that for acute contraction models of mechanical stimuli, there is an emerging pattern suggesting that there is an early increase in protein synthesis governed by a rapamycin-sensitive mTORC1-dependent mechanism, while at later poststimulation time points, the mechanism may change to a rapamycin-insensitive mTORC1-dependent or even an mTORC1-independent mechanism. Furthermore, evidence suggests that mTORC1 appears to be absolutely necessary for muscle fiber hypertrophy induced by chronic mechanical loading but may only play a partial role in the hypertrophy induced by more intermittent types of acute resistance exercise, with the possibility of mTORC1-independent mechanisms also playing a role. Despite the progress that has been made, many questions about the activation of mTORC1, and its downstream targets, remain to be answered. Further research will hopefully provide novel insights into the regulation of skeletal muscle mTORC1 that may eventually be translated into novel exercise programing and/or targeted pharmacological therapies aimed at preventing muscle wasting and/or increasing muscle mass.

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Maslinic acid activates mTORC1 and human TGR5 and induces skeletal muscle hypertrophy

Bioscience Biotechnology and Biochemistry ◽

10.1093/bbb/zbab151 ◽

2021 ◽

Author(s):

Shotaro Murata ◽

Takashi Sasaki ◽

Yuki Yamauchi ◽

Makoto Shimizu ◽

Ryuichiro Sato

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Mammalian Target Of Rapamycin ◽

Standard Diet ◽

Muscular Hypertrophy ◽

Akt Inhibitor ◽

Pentacyclic Triterpene ◽

Maslinic Acid ◽

C2c12 Skeletal Muscle Cells

ABSTRACT Maslinic acid, a naturally occurring pentacyclic triterpene in more than 30 plants (including olives), reportedly increases human muscle mass and muscle strength; however, the underlying molecular mechanism remains unknown. C57BL/6J mice were fed a standard diet or supplemented with 0.27% maslinic acid for 4 weeks, and their skeletal muscle mass was measured. Mice that consumed maslinic acid displayed significant increases in gastrocnemius and soleus muscle mass. Cultured mouse-C2C12 skeletal muscle cells were treated with mammalian target of rapamycin complex 1 (mTORC1) or protein kinase b (Akt) inhibitor, and protein synthesis was quantified. Maslinic acid accelerated protein synthesis via mTORC1 activation independent of Akt. Furthermore, maslinic acid activated human Takeda G protein-coupled receptor 5 (TGR5) more strongly than mouse TGR5, augmenting the expression of several genes related to muscular hypertrophy. Maslinic acid activated mTORC1 and human TGR5, implying its contribution to human muscular hypertrophy through these effects.

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Higher skeletal muscle protein synthesis and lower breakdown after chemotherapy in cachectic mice

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.2001.281.1.r133 ◽

2001 ◽

Vol 281 (1) ◽

pp. R133-R139 ◽

Cited By ~ 20

Author(s):

S. E. Samuels ◽

A. L. Knowles ◽

T. Tilignac ◽

E. Debiton ◽

J. C. Madelmont ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Cancer Cachexia ◽

Muscle Protein ◽

Muscle Protein Synthesis ◽

Human Condition ◽

Skeletal Muscle Protein ◽

Tumor Bearing

The influence of cancer cachexia and chemotherapy and subsequent recovery of skeletal muscle protein mass and turnover was investigated in mice. Cancer cachexia was induced using colon 26 adenocarcinoma, which is characteristic of the human condition, and can be cured with 100% efficacy using an experimental nitrosourea, cystemustine (C6H12CIN3O4S). Reduced food intake was not a factor in these studies. Three days after cachexia began, healthy and tumor-bearing mice were given a single intraperitoneal injection of cystemustine (20 mg/kg). Skeletal muscle mass in tumor-bearing mice was 41% lower ( P < 0.05) than in healthy mice 2 wk after cachexia began. Skeletal muscle wasting was mediated initially by decreased protein synthesis (−38%; P < 0.05) and increased degradation (+131%; P < 0.05); later wasting resulted solely from decreased synthesis (∼−54 to −69%; P < 0.05). Acute cytotoxicity of chemotherapy did not appear to have an important effect on skeletal muscle protein metabolism in either healthy or tumor-bearing mice. Recovery began 2 days after treatment; skeletal muscle mass was only 11% lower than in healthy mice 11 days after chemotherapy. Recovery of skeletal muscle mass was affected initially by decreased protein degradation (−80%; P < 0.05) and later by increased protein synthesis (+46 to +73%; P < 0.05) in cured compared with healthy mice. This study showed that skeletal muscle wasted from cancer cachexia and after chemotherapeutic treatment is able to generate a strong anabolic response by making powerful changes to protein synthesis and degradation.

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Arrdc2 and Arrdc3 elicit divergent changes in gene expression in skeletal muscle following anabolic and catabolic stimuli

Physiological Genomics ◽

10.1152/physiolgenomics.00007.2019 ◽

2019 ◽

Vol 51 (6) ◽

pp. 208-217 ◽

Cited By ~ 2

Author(s):

Bradley S. Gordon ◽

Michael L. Rossetti ◽

Alexey M. Eroshkin

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Tibialis Anterior ◽

Gene Networks ◽

Tibialis Anterior Muscle ◽

The Body ◽

Molecular Networks ◽

Expression Of Genes ◽

Consistent Change ◽

Mechanical Overload

Skeletal muscle is a highly plastic organ regulating various processes in the body. As such, loss of skeletal muscle underlies the increased morbidity and mortality risk that is associated with numerous conditions. However, no therapies are available to combat the loss of muscle mass during atrophic conditions, which is due in part to the incomplete understanding of the molecular networks altered by anabolic and catabolic stimuli. Thus, the current objective was to identify novel gene networks modulated by such stimuli. For this, total RNA from the tibialis anterior muscle of mice that were fasted overnight or fasted overnight and refed the next morning was subjected to microarray analysis. The refeeding stimulus altered the expression of genes associated with signal transduction. Specifically, expression of alpha arrestin domain containing 2 (Arrdc2) and alpha arrestin domain containing 3 (Arrdc3) was significantly lowered 70–85% by refeeding. Subsequent analysis showed that expression of these genes was also lowered 50–75% by mechanical overload, with the combination of nutrients and mechanical overload acting synergistically to lower Arrdc2 and Arrdc3 expression. On the converse, stimuli that suppress growth such as testosterone depletion or acute aerobic exercise increased Arrdc2 and Arrdc3 expression in skeletal muscle. While Arrdc2 and Arrdc3 exhibited divergent changes in expression following anabolic or catabolic stimuli, no other member of the Arrdc family of genes exhibited the consistent change in expression across the analyzed conditions. Thus, Arrdc2 and Arrdc3 are a novel set of genes that may be implicated in the regulation of skeletal muscle mass.

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Absence of insulin signalling in skeletal muscle is associated with reduced muscle mass and function: evidence for decreased protein synthesis and not increased degradation

AGE ◽

10.1007/s11357-009-9125-0 ◽

2010 ◽

Vol 32 (2) ◽

pp. 209-222 ◽

Cited By ~ 24

Author(s):

Elaine D. O’Neill ◽

John P. H. Wilding ◽

C. Ronald Kahn ◽

Holly Van Remmen ◽

Anne McArdle ◽

...

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Muscle Mass ◽

Insulin Signalling ◽

And Function

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Regulation of Ribosome Biogenesis in Skeletal Muscle Hypertrophy

Physiology ◽

10.1152/physiol.00034.2018 ◽

2019 ◽

Vol 34 (1) ◽

pp. 30-42 ◽

Cited By ~ 24

Author(s):

Vandré Casagrande Figueiredo ◽

John J. McCarthy

Keyword(s):

Skeletal Muscle ◽

Protein Synthesis ◽

Ribosome Biogenesis ◽

Muscle Hypertrophy ◽

Muscle Growth ◽

Translational Efficiency ◽

Resistance Exercise Training ◽

Skeletal Muscle Growth ◽

Skeletal Muscle Hypertrophy ◽

Important Regulator

The ribosome is the enzymatic macromolecular machine responsible for protein synthesis. The rates of protein synthesis are primarily dependent on translational efficiency and capacity. Ribosome biogenesis has emerged as an important regulator of skeletal muscle growth and maintenance by altering the translational capacity of the cell. Here, we provide evidence to support a central role for ribosome biogenesis in skeletal muscle growth during postnatal development and in response to resistance exercise training. Furthermore, we discuss the cellular signaling pathways regulating ribosome biogenesis, discuss how myonuclear accretion affects translational capacity, and explore future areas of investigation within the field.

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Effect of postdevelopmental myostatin depletion on myofibrillar protein metabolism

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00509.2010 ◽

2011 ◽

Vol 300 (6) ◽

pp. E993-E1001 ◽

Cited By ~ 13

Author(s):

Stephen Welle ◽

Sangeeta Mehta ◽

Kerri Burgess

Keyword(s):

Protein Synthesis ◽

Food Deprivation ◽

Muscle Hypertrophy ◽

Ring Finger ◽

Quadriceps Muscle ◽

Rate Of Change ◽

Synthesis Rate ◽

Ribosomal Protein S6 ◽

Degradation Rates ◽

The Difference

It is unclear whether the muscle hypertrophy induced by loss of myostatin signaling in mature muscles is maintained only by increased protein synthesis or whether reduced proteolysis contributes. To address this issue, we depleted myostatin by activating Cre recombinase for 2 wk in mature mice in which Mstn exon 3 was flanked by loxP sequences. The rate of phenylalanine tracer incorporation into myofibrillar proteins was determined 2, 5, and 24 wk after Cre activation ended. At all of these time points, myostatin-deficient mice had increased gastrocnemius and quadriceps muscle mass (≥27%) and increased myofibrillar synthesis rate per gastrocnemius muscle (≥19%) but normal myofibrillar synthesis rates per myofibrillar mass or RNA mass. Mean fractional myofibrillar degradation rates (estimated from the difference between rate of synthesis and rate of change in myofibrillar mass) and muscle concentrations of free 3-methylhistidine (from actin and myosin degradation) were unaffected by myostatin knockout. Overnight food deprivation reduced myofibrillar synthesis and ribosomal protein S6 phosphorylation and increased concentrations of 3-methylhistidine, muscle RING finger-1 mRNA, and atrogin-1 mRNA. Myostatin depletion did not affect these responses to food deprivation. These data indicate that maintenance of the muscle hypertrophy caused by loss of myostatin is mediated by increased protein synthesis per muscle fiber rather than suppression of proteolysis.

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Role of PDK1 in skeletal muscle hypertrophy induced by mechanical load

Scientific Reports ◽

10.1038/s41598-021-83098-z ◽

2021 ◽

Vol 11 (1) ◽

Cited By ~ 1

Author(s):

Naoki Kuramoto ◽

Kazuhiro Nomura ◽

Daisuke Kohno ◽

Tadahiro Kitamura ◽

Gerard Karsenty ◽

...

Keyword(s):

Gene Expression ◽

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Hypertrophy ◽

Mechanical Load ◽

Static Condition ◽

Ribosomal Protein S6 ◽

Pi3k Signaling Pathway ◽

Induced Changes

AbstractPhosphatidylinositol 3-kinase (PI3K) plays an important role in protein metabolism and cell growth. We here show that mice (M-PDK1KO mice) with skeletal muscle–specific deficiency of 3′-phosphoinositide–dependent kinase 1 (PDK1), a key component of PI3K signaling pathway, manifest a reduced skeletal muscle mass under the static condition as well as impairment of mechanical load–induced muscle hypertrophy. Whereas mechanical load-induced changes in gene expression were not affected, the phosphorylation of ribosomal protein S6 kinase (S6K) and S6 induced by mechanical load was attenuated in skeletal muscle of M-PDK1KO mice, suggesting that PDK1 regulates muscle hypertrophy not through changes in gene expression but through stimulation of kinase cascades such as the S6K-S6 axis, which plays a key role in protein synthesis. Administration of the β2-adrenergic receptor (AR) agonist clenbuterol activated the S6K-S6 axis in skeletal muscle and induced muscle hypertrophy in mice. These effects of clenbuterol were attenuated in M-PDK1KO mice, and mechanical load–induced activation of the S6K-S6 axis and muscle hypertrophy were inhibited in mice with skeletal muscle–specific deficiency of β2-AR. Our results suggest that PDK1 regulates skeletal muscle mass under the static condition and that it contributes to mechanical load–induced muscle hypertrophy, at least in part by mediating signaling from β2-AR.

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