Hypoxia transiently affects skeletal muscle hypertrophy in a functional overload model

2012 ◽  
Vol 302 (5) ◽  
pp. R643-R654 ◽  
Author(s):  
Thomas Chaillou ◽  
Nathalie Koulmann ◽  
Nadine Simler ◽  
Adélie Meunier ◽  
Bernard Serrurier ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signaling Pathways ◽  
Muscle Hypertrophy ◽  
Molecular Mechanisms ◽  
Muscle Growth ◽  
Female Rats ◽  
Mrna Levels ◽  
Hypertrophic Response ◽  
Protein Levels ◽  
Skeletal Muscle Hypertrophy

Hypoxia induces a loss of skeletal muscle mass, but the signaling pathways and molecular mechanisms involved remain poorly understood. We hypothesized that hypoxia could impair skeletal muscle hypertrophy induced by functional overload (Ov). To test this hypothesis, plantaris muscles were overloaded during 5, 12, and 56 days in female rats exposed to hypobaric hypoxia (5,500 m), and then, we examined the responses of specific signaling pathways involved in protein synthesis (Akt/mTOR) and breakdown (atrogenes). Hypoxia minimized the Ov-induced hypertrophy at days 5 and 12 but did not affect the hypertrophic response measured at day 56. Hypoxia early reduced the phosphorylation levels of mTOR and its downstream targets P70S6K and rpS6, but it did not affect the phosphorylation levels of Akt and 4E-BP1, in Ov muscles. The role played by specific inhibitors of mTOR, such as AMPK and hypoxia-induced factors (i.e., REDD1 and BNIP-3) was studied. REDD1 protein levels were reduced by overload and were not affected by hypoxia in Ov muscles, whereas AMPK was not activated by hypoxia. Although hypoxia significantly increased BNIP-3 mRNA levels at day 5, protein levels remained unaffected. The mRNA levels of the two atrogenes MURF1 and MAFbx were early increased by hypoxia in Ov muscles. In conclusion, hypoxia induced a transient alteration of muscle growth in this hypertrophic model, at least partly due to a specific impairment of the mTOR/P70S6K pathway, independently of Akt, by an undefined mechanism, and increased transcript levels for MURF1 and MAFbx that could contribute to stimulate the proteasomal proteolysis.

scholarly journals AMPKγ3 is dispensable for skeletal muscle hypertrophy induced by functional overload

2016 ◽  
Vol 310 (6) ◽  
pp. E461-E472 ◽  
Author(s):  
Isabelle Riedl ◽  
Megan E. Osler ◽  
Marie Björnholm ◽  
Brendan Egan ◽  
Gustavo A. Nader ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Signaling Pathways ◽  
Muscle Hypertrophy ◽  
Muscle Growth ◽  
Mammalian Target Of Rapamycin ◽  
Growth Control ◽  
Mass Gain ◽  
Mtor Signaling ◽  
Wild Type ◽  
Skeletal Muscle Hypertrophy

Mechanisms regulating skeletal muscle growth involve a balance between the activity of serine/threonine protein kinases, including the mammalian target of rapamycin (mTOR) and 5′-AMP-activated protein kinase (AMPK). The contribution of different AMPK subunits to the regulation of cell growth size remains inadequately characterized. Using AMPKγ3 mutant-overexpressing transgenic Tg-Prkag3 225Q and AMPKγ3-knockout ( Prkag3−/−) mice, we investigated the requirement for the AMPKγ3 isoform in functional overload-induced muscle hypertrophy. Although the genetic disruption of the γ3 isoform did not impair muscle growth, control sham-operated AMPKγ3-transgenic mice displayed heavier plantaris muscles in response to overload hypertrophy and underwent smaller mass gain and lower Igf1 expression compared with wild-type littermates. The mTOR signaling pathway was upregulated with functional overload but unchanged between genetically modified animals and wild-type littermates. Differences in AMPK-related signaling pathways between transgenic, knockout, and wild-type mice did not impact muscle hypertrophy. Glycogen content was increased following overload in wild-type mice. In conclusion, our functional, transcriptional, and signaling data provide evidence against the involvement of the AMPKγ3 isoform in the regulation of skeletal muscle hypertrophy. Thus, the AMPKγ3 isoform is dispensable for functional overload-induced muscle growth. Mechanical loading can override signaling pathways that act as negative effectors of mTOR signaling and consequently promote skeletal muscle hypertrophy.

scholarly journals Molecular Mechanisms of Skeletal Muscle Hypertrophy

2020 ◽  
pp. 1-15
Author(s):  
Stefano Schiaffino ◽  
Carlo Reggiani ◽  
Takayuki Akimoto ◽  
Bert Blaauw
Keyword(s):  
Skeletal Muscle ◽  
Protein Synthesis ◽  
Muscle Hypertrophy ◽  
Molecular Mechanisms ◽  
Muscle Growth ◽  
Transcriptional Level ◽  
Ribosomal Biogenesis ◽  
Skeletal Muscle Hypertrophy ◽  
Positive Regulators ◽  
Exercise Muscle

Skeletal muscle hypertrophy can be induced by hormones and growth factors acting directly as positive regulators of muscle growth or indirectly by neutralizing negative regulators, and by mechanical signals mediating the effect of resistance exercise. Muscle growth during hypertrophy is controlled at the translational level, through the stimulation of protein synthesis, and at the transcriptional level, through the activation of ribosomal RNAs and muscle-specific genes. mTORC1 has a central role in the regulation of both protein synthesis and ribosomal biogenesis. Several transcription factors and co-activators, including MEF2, SRF, PGC-1α4, and YAP promote the growth of the myofibers. Satellite cell proliferation and fusion is involved in some but not all muscle hypertrophy models.

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 Regulation of Ribosome Biogenesis in Skeletal Muscle Hypertrophy

Physiology ◽  
2019 ◽  
Vol 34 (1) ◽  
pp. 30-42 ◽  
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.

scholarly journals p21-Activated Kinase 1 Is Permissive for the Skeletal Muscle Hypertrophy Induced by Myostatin Inhibition

2021 ◽  
Vol 12 ◽  
Author(s):  
Caroline Barbé ◽  
Audrey Loumaye ◽  
Pascale Lause ◽  
Olli Ritvos ◽  
Jean-Paul Thissen
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Muscle Hypertrophy ◽  
Molecular Mechanisms ◽  
Muscle Development ◽  
The Body ◽  
Negative Regulator ◽  
Skeletal Muscle Hypertrophy ◽  
Myostatin Inhibition

Skeletal muscle, the most abundant tissue in the body, plays vital roles in locomotion and metabolism. Understanding the cellular processes that govern regulation of muscle mass and function represents an essential step in the development of therapeutic strategies for muscular disorders. Myostatin, a member of the TGF-β family, has been identified as a negative regulator of muscle development. Indeed, its inhibition induces an extensive skeletal muscle hypertrophy requiring the activation of Smad 1/5/8 and the Insulin/IGF-I signaling pathway, but whether other molecular mechanisms are involved in this process remains to be determined. Using transcriptomic data from various Myostatin inhibition models, we identified Pak1 as a potential mediator of Myostatin action on skeletal muscle mass. Our results show that muscle PAK1 levels are systematically increased in response to Myostatin inhibition, parallel to skeletal muscle mass, regardless of the Myostatin inhibition model. Using Pak1 knockout mice, we investigated the role of Pak1 in the skeletal muscle hypertrophy induced by different approaches of Myostatin inhibition. Our findings show that Pak1 deletion does not impede the skeletal muscle hypertrophy magnitude in response to Myostatin inhibition. Therefore, Pak1 is permissive for the skeletal muscle mass increase caused by Myostatin inhibition.

Mechanical loading induces the expression of a Pol I regulon at the onset of skeletal muscle hypertrophy

2012 ◽  
Vol 302 (10) ◽  
pp. C1523-C1530 ◽  
Author(s):  
Ferdinand von Walden ◽  
Vandre Casagrande ◽  
Ann-Kristin Östlund Farrants ◽  
Gustavo A. Nader
Keyword(s):  
Skeletal Muscle ◽  
Mechanical Loading ◽  
Muscle Hypertrophy ◽  
Rrna Synthesis ◽  
Rdna Transcription ◽  
Hypertrophic Response ◽  
Skeletal Muscle Hypertrophy ◽  
Pol I ◽  
Upstream Binding Factor ◽  
Polymerase I

The main goal of the present study was to investigate the regulation of ribosomal DNA (rDNA) gene transcription at the onset of skeletal muscle hypertrophy. Mice were subjected to functional overload of the plantaris by bilateral removal of the synergist muscles. Mechanical loading resulted in muscle hypertrophy with an increase in rRNA content. rDNA transcription, as determined by 45S pre-rRNA abundance, paralleled the increase in rRNA content and was consistent with the onset of the hypertrophic response. Increased transcription and protein expression of c-Myc and its downstream polymerase I (Pol I) regulon (POL1RB, TIF-1A, PAF53, TTF1, TAF1C) was also consistent with the increase in rRNA. Similarly, factors involved in rDNA transcription, such as the upstream binding factor and the Williams syndrome transcription factor, were induced by mechanical loading in a corresponding temporal fashion. Chromatin immunoprecipitation revealed that these factors, together with Pol I, were enriched at the rDNA promoter. This, in addition to an increase in histone H3 lysine 9 acetylation, demonstrates that mechanical loading regulates rRNA synthesis by inducing a gene expression program consisting of a Pol I regulon, together with accessory factors involved in transcription and chromatin remodeling at the rDNA promoter. Altogether, these data indicate that transcriptional and epigenetic mechanisms take place in the regulation of ribosome production at the onset of muscle hypertrophy.

scholarly journals COX-2 inhibitor reduces skeletal muscle hypertrophy in mice

2009 ◽  
Vol 296 (4) ◽  
pp. R1132-R1139 ◽  
Author(s):  
Margaret L Novak ◽  
William Billich ◽  
Sierra M. Smith ◽  
Kunal B. Sukhija ◽  
Thomas J. McLoughlin ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cell Proliferation ◽  
Muscle Hypertrophy ◽  
Muscle Growth ◽  
Muscular Activity ◽  
Compensatory Hypertrophy ◽  
Cell Nuclei ◽  
Skeletal Muscle Hypertrophy ◽  
Cox 2 ◽  
Macrophage Accumulation

Anti-inflammatory strategies are often used to reduce muscle pain and soreness that can result from high-intensity muscular activity. However, studies indicate that components of the acute inflammatory response may be required for muscle repair and growth. The hypothesis of this study was that cyclooxygenase (COX)-2 activity is required for compensatory hypertrophy of skeletal muscle. We used the synergist ablation model of skeletal muscle hypertrophy, along with the specific COX-2 inhibitor NS-398, to investigate the role of COX-2 in overload-induced muscle growth in mice. COX-2 was expressed in plantaris muscles during compensatory hypertrophy and was localized mainly in or near muscle cell nuclei. Treatment with NS-398 blunted the increases in mass and protein content in overloaded muscles compared with vehicle-treated controls. Additionally, the COX-2 inhibitor decreased activity of the urokinase type plasminogen activator, macrophage accumulation, and cell proliferation, all of which are required for hypertrophy after synergist ablation. Expression of insulin-like growth factor-1 and phosphorylation of Akt, mammalian target of rapamycin, and p70S6K were increased following synergist ablation, but were not affected by NS-398. Additionally, expression of atrogin-1 was reduced during hypertrophy, but was also not affected by NS-398. These results demonstrate that COX-2 activity is required for skeletal muscle hypertrophy, possibly through facilitation of extracellular protease activity, macrophage accumulation, and cell proliferation.

scholarly journals Regulation of myosin heavy-chain gene expression during skeletal-muscle hypertrophy

1989 ◽  
Vol 257 (3) ◽  
pp. 691-698 ◽  
Author(s):  
M Periasamy ◽  
P Gregory ◽  
B J Martin ◽  
W S Stirewalt
Keyword(s):  
Skeletal Muscle ◽  
Muscle Hypertrophy ◽  
Compensatory Hypertrophy ◽  
Chain Gene ◽  
Mrna Levels ◽  
Muscle Adaptation ◽  
Myosin Heavy Chain Gene ◽  
Rat Skeletal Muscle ◽  
Skeletal Muscle Hypertrophy ◽  
Myosin Isoenzymes

Changes in the myosin phenotype of differentiated muscle are a prominent feature of the adaptation of the tissue to a variety of physiological stimuli. In the present study the molecular basis of changes in the proportion of myosin isoenzymes in rat skeletal muscle which occur during compensatory hypertrophy caused by the combined removal of synergist muscles and spontaneous running exercise was investigated. The relative amounts of sarcomeric myosin heavy (MHC)- and light (MLC)-chain mRNAs in the plantaris (fast) and soleus (slow) muscles from rats was assessed with cDNA probes specific for different MHC and MLC genes. Changes in the proportion of specific MHC mRNA levels were in the same direction as, and of similar magnitude to, changes in the proportion of myosin isoenzymes encoded for by the mRNAs. No significant changes in the proportion of MLC proteins or mRNA were detected. However, high levels of MLC3 mRNA were measured in both normal and hypertrophied soleus muscles which contained only trace amounts of MLC3 protein. Small amounts of embryonic and neonatal MHC mRNAs were induced in both muscles during hypertrophy. We conclude that the change in the pattern of myosin isoenzymes during skeletal-muscle adaptation to work overload is a consequence of changes in specific MHC mRNA levels.

scholarly journals The relationships among IGF-1, DNA content, and protein accumulation during skeletal muscle hypertrophy

1996 ◽  
Vol 81 (6) ◽  
pp. 2509-2516 ◽  
Author(s):  
G. R. Adams ◽  
F. Haddad
Keyword(s):  
Skeletal Muscle ◽  
Dna Content ◽  
Time Course ◽  
Muscle Hypertrophy ◽  
Weight Ratio ◽  
Surgical Removal ◽  
Protein Accumulation ◽  
Hypertrophic Response ◽  
Skeletal Muscle Hypertrophy ◽  
Strong Positive Relationship

Adams, G. R., and F. Haddad. The relationships among IGF-1, DNA content, and protein accumulation during skeletal muscle hypertrophy. J. Appl. Physiol. 81(6): 2509–2516, 1996.—Insulin-like growth factor-1 (IGF-1) is known to have anabolic effects on skeletal muscle cells. This study examined the time course of muscle hypertrophy and associated IGF-1 peptide and mRNA expression. Data were collected at 3, 7, 14, and 28 days after surgical removal of synergistic muscles of both normal and hypophysectomized (HX) animals. Overloading increased the plantaris (Plant) mass, myofiber size, and protein-to-body weight ratio in both groups (normal and HX; P < 0.05). Muscle IGF-1 peptide levels peaked at 3 (normal) and 7 (HX) days of overloading with maximum 4.1-fold (normal) and 6.2-fold (HX) increases. Increases in muscle IGF-1 preceded the hypertrophic response. Total DNA content of the overloaded Plant increased in both groups. There was a strong positive relationship between IGF-1 peptide and DNA content in the overloaded Plant from both groups. These results indicate that 1) the muscles from rats with both normal and severely depressed systemic levels of IGF-1 respond to functional overload with an increase in local IGF-1 expression and 2) this elevated IGF-1 may be contributing to the hypertrophy response, possibly via the mobilization of satellite cells to provide increases in muscle DNA.

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