Determinants of Skeletal Muscle Hypertrophy and the Attenuated Hypertrophic Response at Old Age

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.

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

Journal of Applied Physiology ◽

10.1152/jappl.1996.81.6.2509 ◽

1996 ◽

Vol 81 (6) ◽

pp. 2509-2516 ◽

Cited By ~ 188

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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A Phosphatidylinositol 3-Kinase/Protein Kinase B-independent Activation of Mammalian Target of Rapamycin Signaling Is Sufficient to Induce Skeletal Muscle Hypertrophy

Molecular Biology of the Cell ◽

10.1091/mbc.e10-05-0454 ◽

2010 ◽

Vol 21 (18) ◽

pp. 3258-3268 ◽

Cited By ~ 76

Author(s):

Craig A. Goodman ◽

Man Hing Miu ◽

John W. Frey ◽

Danielle M. Mabrey ◽

Hannah C. Lincoln ◽

...

Keyword(s):

Skeletal Muscle ◽

Sensitive Element ◽

Muscle Hypertrophy ◽

Kinase Activity ◽

Protein Kinase B ◽

Mammalian Target Of Rapamycin ◽

Mtor Signaling ◽

Phosphatidylinositol 3 Kinase ◽

Hypertrophic Response ◽

Skeletal Muscle Hypertrophy

It has been widely proposed that signaling by mammalian target of rapamycin (mTOR) is both necessary and sufficient for the induction of skeletal muscle hypertrophy. Evidence for this hypothesis is largely based on studies that used stimuli that activate mTOR via a phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB)-dependent mechanism. However, the stimulation of signaling by PI3K/PKB also can activate several mTOR-independent growth-promoting events; thus, it is not clear whether signaling by mTOR is permissive, or sufficient, for the induction of hypertrophy. Furthermore, the presumed role of mTOR in hypertrophy is derived from studies that used rapamycin to inhibit mTOR; yet, there is very little direct evidence that mTOR is the rapamycin-sensitive element that confers the hypertrophic response. In this study, we determined that, in skeletal muscle, overexpression of Rheb stimulates a PI3K/PKB-independent activation of mTOR signaling, and this is sufficient for the induction of a rapamycin-sensitive hypertrophic response. Transgenic mice with muscle specific expression of various mTOR mutants also were used to demonstrate that mTOR is the rapamycin-sensitive element that conferred the hypertrophic response and that the kinase activity of mTOR is necessary for this event. Combined, these results provide direct genetic evidence that a PI3K/PKB-independent activation of mTOR signaling is sufficient to induce hypertrophy. In summary, overexpression of Rheb activates mTOR signaling via a PI3K/PKB-independent mechanism and is sufficient to induce skeletal muscle hypertrophy. The hypertrophic effects of Rheb are driven through a rapamycin-sensitive (RS) mechanism, mTOR is the RS element that confers the hypertrophy, and the kinase activity of mTOR is necessary for this event.

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Hypoxia transiently affects skeletal muscle hypertrophy in a functional overload model

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00262.2011 ◽

2012 ◽

Vol 302 (5) ◽

pp. R643-R654 ◽

Cited By ~ 25

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.

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ANG II is required for optimal overload-induced skeletal muscle hypertrophy

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.2001.280.1.e150 ◽

2001 ◽

Vol 280 (1) ◽

pp. E150-E159 ◽

Cited By ~ 80

Author(s):

Scott E. Gordon ◽

Bradley S. Davis ◽

Christian J. Carlson ◽

Frank W. Booth

Keyword(s):

Skeletal Muscle ◽

Soleus Muscle ◽

Muscle Hypertrophy ◽

Ace Inhibitor ◽

Muscle Protein ◽

Ang Ii ◽

Sprague Dawley ◽

Surgical Ablation ◽

Hypertrophic Response ◽

Skeletal Muscle Hypertrophy

ANG II mediates the hypertrophic response of overloaded cardiac muscle, likely via the ANG II type 1 (AT1) receptor. To examine the potential role of ANG II in overload-induced skeletal muscle hypertrophy, plantaris and/or soleus muscle overload was produced in female Sprague-Dawley rats (225–250 g) by the bilateral surgical ablation of either the synergistic gastrocnemius muscle ( experiment 1) or both the gastrocnemius and plantaris muscles ( experiment 2). In experiment 1 ( n = 10/ group), inhibiting endogenous ANG II production by oral administration of an angiotensin-converting enzyme (ACE) inhibitor during a 28-day overloading protocol attenuated plantaris and soleus muscle hypertrophy by 57 and 96%, respectively (as measured by total muscle protein content). ACE inhibition had no effect on nonoverloaded (sham-operated) muscles. With the use of new animals ( experiment 2; n = 8/group), locally perfusing overloaded soleus muscles with exogenous ANG II (via osmotic pump) rescued the lost hypertrophic response in ACE-inhibited animals by 71%. Furthermore, orally administering an AT1 receptor antagonist instead of an ACE inhibitor produced a 48% attenuation of overload-induced hypertrophy that could not be rescued by ANG II perfusion. Thus ANG II may be necessary for optimal overload-induced skeletal muscle hypertrophy, acting at least in part via an AT1receptor-dependent pathway.

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The Effect of Low-Load Resistance Training on Skeletal Muscle Hypertrophy in Trained Men: A Critically Appraised Topic

Journal of Sport Rehabilitation ◽

10.1123/jsr.2020-0504 ◽

2021 ◽

pp. 1-6

Author(s):

Nick Dobson

Keyword(s):

Skeletal Muscle ◽

Resistance Training ◽

Muscle Hypertrophy ◽

Physiological Stress ◽

High Load ◽

High Threshold ◽

Bottom Line ◽

Hypertrophic Response ◽

Skeletal Muscle Hypertrophy ◽

Low Load

Clinical Scenario: Resistance training (RT) programs promote skeletal muscle hypertrophy through the progressive physiological stress applied to an individual. Currently, the vast majority of studies regarding the hypertrophic response to RT have focused on either sedentary or untrained individuals. This critically appraised topic focuses on the hypertrophic response to high- and low-load RT in resistance-trained men. Clinical Question: In experienced male weightlifters, does high-load RT lead to greater increases in muscle mass than low-load RT? Summary of Key Findings: Six studies met the inclusion criteria, while 4 studies were included in the analysis. Each of the 4 studies showed that low-load RT elicited hypertrophic gains similar to high-load RT when sets were taken to failure. Three of the studies were not volume equated, indicating a dose–response relationship between training volume-load and skeletal muscle hypertrophy. One of the studies was volume equated, indicating that skeletal muscle hypertrophy could be achieved at levels comparable to those observed in high-load protocols as a result of high levels of metabolic stress and the concomitant recruitment of high-threshold motor units that can occur during fatiguing contractions. Clinical Bottom Line: Evidence suggests that low-load training produces hypertrophic gains similar to those observed in high-load RT protocols when sets are taken to failure in resistance-trained men. Strength of Recommendation: There is moderate to strong evidence to suggest that low-load RT elicits hypertrophic gains similar to those observed in high-load RT protocols when sets are taken to failure in resistance-trained men.

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Lower and Higher Load Resistance Exercise Protocols: Acute Muscle Activation and Skeletal Muscle Hypertrophy

Case Medical Research ◽

10.31525/ct1-nct03991117 ◽

2019 ◽

Author(s):

Keyword(s):

Skeletal Muscle ◽

Resistance Exercise ◽

Muscle Activation ◽

Muscle Hypertrophy ◽

Load Resistance ◽

Skeletal Muscle Hypertrophy

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Hypertrophy of Rat Skeletal Muscle Is Associated with Increased SIRT1/Akt/mTOR/S6 and Suppressed Sestrin2/SIRT3/FOXO1 Levels

International Journal of Molecular Sciences ◽

10.3390/ijms22147588 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7588

Author(s):

Zoltan Gombos ◽

Erika Koltai ◽

Ferenc Torma ◽

Peter Bakonyi ◽

Attila Kolonics ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Hypertrophy ◽

Male Rats ◽

Cellular Interactions ◽

Molecular Signaling ◽

Protein Breakdown ◽

Rat Skeletal Muscle ◽

Plantaris Muscle ◽

Skeletal Muscle Hypertrophy ◽

Intensive Investigation

Despite the intensive investigation of the molecular mechanism of skeletal muscle hypertrophy, the underlying signaling processes are not completely understood. Therefore, we used an overload model, in which the main synergist muscles (gastrocnemius, soleus) of the plantaris muscle were surgically removed, to cause a significant overload in the remaining plantaris muscle of 8-month-old Wistar male rats. SIRT1-associated pro-anabolic, pro-catabolic molecular signaling pathways, NAD and H2S levels of this overload-induced hypertrophy were studied. Fourteen days of overload resulted in a significant 43% (p < 0.01) increase in the mass of plantaris muscle compared to sham operated animals. Cystathionine-β-synthase (CBS) activities and bioavailable H2S levels were not modified by overload. On the other hand, overload-induced hypertrophy of skeletal muscle was associated with increased SIRT1 (p < 0.01), Akt (p < 0.01), mTOR, S6 (p < 0.01) and suppressed sestrin 2 levels (p < 0.01), which are mostly responsible for anabolic signaling. Decreased FOXO1 and SIRT3 signaling (p < 0.01) suggest downregulation of protein breakdown and mitophagy. Decreased levels of NAD+, sestrin2, OGG1 (p < 0.01) indicate that the redox milieu of skeletal muscle after 14 days of overloading is reduced. The present investigation revealed novel cellular interactions that regulate anabolic and catabolic processes in the hypertrophy of skeletal muscle.

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