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.

scholarly journals Recent advances in understanding resistance exercise training-induced skeletal muscle hypertrophy in humans

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 141 ◽  
Author(s):  
Sophie Joanisse ◽  
Changhyun Lim ◽  
James McKendry ◽  
Jonathan C. Mcleod ◽  
Tanner Stokes ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Resistance Exercise ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Muscle Hypertrophy ◽  
Resistance Exercise Training ◽  
Skeletal Muscle Hypertrophy ◽  
Recent Advances ◽  
Development And Utilization ◽  
Exercise Induced

Skeletal muscle plays a pivotal role in the maintenance of physical and metabolic health and, critically, mobility. Accordingly, strategies focused on increasing the quality and quantity of skeletal muscle are relevant, and resistance exercise is foundational to the process of functional hypertrophy. Much of our current understanding of skeletal muscle hypertrophy can be attributed to the development and utilization of stable isotopically labeled tracers. We know that resistance exercise and sufficient protein intake act synergistically and provide the most effective stimuli to enhance skeletal muscle mass; however, the molecular intricacies that underpin the tremendous response variability to resistance exercise-induced hypertrophy are complex. The purpose of this review is to discuss recent studies with the aim of shedding light on key regulatory mechanisms that dictate hypertrophic gains in skeletal muscle mass. We also aim to provide a brief up-to-date summary of the recent advances in our understanding of skeletal muscle hypertrophy in response to resistance training in humans.

scholarly journals Role of IGF-I in follistatin-induced skeletal muscle hypertrophy

2015 ◽  
Vol 309 (6) ◽  
pp. E557-E567 ◽  
Author(s):  
Caroline Barbé ◽  
Stéphanie Kalista ◽  
Audrey Loumaye ◽  
Olli Ritvos ◽  
Pascale Lause ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Muscle Hypertrophy ◽  
Muscle Growth ◽  
Skeletal Muscle Hypertrophy ◽  
Low Concentrations ◽  
Igf I

Follistatin, a physiological inhibitor of myostatin, induces a dramatic increase in skeletal muscle mass, requiring the type 1 IGF-I receptor/Akt/mTOR pathway. The aim of the present study was to investigate the role of IGF-I and insulin, two ligands of the IGF-I receptor, in the follistatin hypertrophic action on skeletal muscle. In a first step, we showed that follistatin increases muscle mass while being associated with a downregulation of muscle IGF-I expression. In addition, follistatin retained its full hypertrophic effect toward muscle in hypophysectomized animals despite very low concentrations of circulating and muscle IGF-I. Furthermore, follistatin did not increase muscle sensitivity to IGF-I in stimulating phosphorylation of Akt but, surprisingly, decreased it once hypertrophy was present. Taken together, these observations indicate that increased muscle IGF-I production or sensitivity does not contribute to the muscle hypertrophy caused by follistatin. Unlike low IGF-I, low insulin, as obtained by streptozotocin injection, attenuated the hypertrophic action of follistatin on skeletal muscle. Moreover, the full anabolic response to follistatin was restored in this condition by insulin but also by IGF-I infusion. Therefore, follistatin-induced muscle hypertrophy requires the activation of the insulin/IGF-I pathway by either insulin or IGF-I. When insulin or IGF-I alone is missing, follistatin retains its full anabolic effect, but when both are deficient, as in streptozotocin-treated animals, follistatin fails to stimulate muscle growth.

scholarly journals Protein Intake and Exercise-Induced Skeletal Muscle Hypertrophy: An Update

Nutrients ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 2023
Author(s):  
Louise Deldicque
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Protein Intake ◽  
Skeletal Muscle Mass ◽  
Muscle Hypertrophy ◽  
Sport Performance ◽  
Skeletal Muscle Hypertrophy ◽  
Exercise Induced ◽  
Net Protein

Skeletal muscle mass is critical for sport performance and in many pathological conditions. The combination of protein intake and resistance exercise is the most efficient strategy to promote skeletal muscle hypertrophy and remodeling. However, to be really efficient, certain conditions need to be considered. The amount, type and source of proteins do all matter as well as the timing of ingestion and spreading over the whole day. Optimizing those conditions favor a positive net protein balance, which in the long term, may result in muscle mass accretion. Last but not least, it is also essential to take the nutritional status and the exercise training load into consideration when looking for maintenance or gain of skeletal muscle mass.

scholarly journals Akt1 deficiency diminishes skeletal muscle hypertrophy by reducing satellite cell proliferation

2018 ◽  
Vol 314 (5) ◽  
pp. R741-R751 ◽  
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.

scholarly journals Activin-type II receptor B (ACVR2B) and follistatin haplotype associations with muscle mass and strength in humans

2007 ◽  
Vol 102 (6) ◽  
pp. 2142-2148 ◽  
Author(s):  
Sean Walsh ◽  
E. Jeffrey Metter ◽  
Luigi Ferrucci ◽  
Stephen M. Roth
Keyword(s):  
Skeletal Muscle ◽  
Genetic Variation ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
Fat Free Mass ◽  
Negative Regulator ◽  
Interindividual Variation ◽  
Whole Body ◽  
Haplotype Structure ◽  
Type Ii

Genetic variation in myostatin, a negative regulator of skeletal muscle, in cattle has shown remarkable influence on skeletal muscle, resulting in a double-muscled phenotype in certain breeds; however, DNA sequence variation within this gene in humans has not been consistently associated with skeletal muscle mass or strength. Follistatin and activin-type II receptor B ( ACVR2B) are two myostatin-related genes involved in the regulation and signaling of myostatin. We sought to identify associations between genetic variation and haplotype structure in both follistatin and ACVR2B with skeletal muscle-related phenotypes. Three hundred fifteen men and 278 women aged 19–90 yr from the Baltimore Longitudinal Study of Aging were genotyped to determine respective haplotype groupings (Hap Groups) based on HapMap data. Whole body soft tissue composition was measured by dual-energy X-ray absorptiometry. Quadriceps peak torque (strength) was measured using an isokinetic dynamometer. Women carriers of ACVR2B Hap Group 1 exhibited significantly less quadriceps muscle strength (shortening phase) than women homozygous for Hap Group 2 (109.2 ± 1.9 vs. 118.6 ± 4.1 N·m, 30°/s, respectively, P = 0.036). No significant association was observed in men. Male carriers of follistatin Hap Group 3 exhibited significantly less total leg fat-free mass than noncarriers (16.6 ± 0.3 vs. 17.5 ± 0.2 kg, respectively, P = 0.012). No significant associations between these haplotype groups were observed in women. These results indicate that haplotype structure at the ACVR2B and follistatin loci may contribute to interindividual variation in skeletal muscle mass and strength, although these data indicate sex-specific relationships.

scholarly journals The Association between Serum Uric Acid and Appendicular Skeletal Muscle Mass and the Effect of Their Interaction on Mortality in Patients on Peritoneal Dialysis

2020 ◽  
Vol 45 (6) ◽  
pp. 969-981
Author(s):  
Xi Xiao ◽  
Chunyan Yi ◽  
Yuan Peng ◽  
Hongjian Ye ◽  
Haishan Wu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Uric Acid ◽  
Peritoneal Dialysis ◽  
Serum Uric Acid ◽  
Muscle Mass ◽  
Skeletal Muscle Mass ◽  
The Body ◽  
All Cause Mortality ◽  
Appendicular Skeletal Muscle ◽  
Appendicular Skeletal Muscle Mass

<b><i>Background:</i></b> Serum uric acid (SUA) has been revealed to be positively associated with the body composition parameters in hemodialysis patients, but few studies have investigated that in patients on peritoneal dialysis (PD). The aim of this study was to identify the relationship between SUA and appendicular skeletal muscle mass (ASM) and the effect of their interaction on mortality in PD patients. <b><i>Methods:</i></b> This was a single-center retrospective cohort study. Patients who underwent multifrequency bioelectrical impedance analysis between January 1, 2013, and December 31, 2016, and had data on SUA values were enrolled. All patients were followed up until December 31, 2019. <b><i>Results:</i></b> In total, 802 prevalent PD patients (57.9% male), with mean age of 46.2 ± 14.2 years were enrolled. The average SUA and ASM were 6.8 ± 1.3 mg/dL and 21.2 ± 4.9 kg. According to multiple linear regression models, SUA was positively associated with relative ASM in middle-aged and older PD patients (standardized coefficients [β] 0.117; 95% confidence interval [CI] 0.027, 0.200; <i>p</i> = 0.010). Further sex-stratified analysis showed that the association existed only in males (β 0.161; 95% CI 0.017, 0.227; <i>p</i> = 0.023). Moreover, the presence of hyperuricemia was found to predict lower risk of all-cause mortality (hazard ratio [HR] 0.514, 95% CI 0.272, 0.970; <i>p</i> = 0.040) only in patients with lower relative ASM. And, the adjusted HR of every 1 mg/dL elevated SUA level was 0.770 (95% CI 0.609, 0.972; <i>p</i> = 0.028) for all-cause mortality in the lower relative ASM subgroup. <b><i>Conclusions:</i></b> There exists a positive association between the SUA and ASM, and the ASM significantly affected the association between SUA and all-cause PD mortality.

scholarly journals Role of PDK1 in skeletal muscle hypertrophy induced by mechanical load

2021 ◽  
Vol 11 (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.

Growth differentiation factor 15 (GDF-15) inhibition to increase muscle mass and function in cancer cachexia.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15633-e15633
Author(s):  
Matthew Peloquin ◽  
Brianna LaCarubba ◽  
Stephanie Joaqium ◽  
Gregory Weber ◽  
John Stansfield ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Muscle Mass ◽  
Muscle Function ◽  
Skeletal Muscle Mass ◽  
Cancer Cachexia ◽  
Tumor Model ◽  
Growth Differentiation Factor 15 ◽  
Myostatin Inhibition ◽  
And Function

e15633 Background: Almost half of cancer deaths are attributed to cancers most frequently associated with cachexia. Cachexia is a complex metabolic disease characterized by anorexia and unintentional weight loss. Skeletal muscle depletion has been recognized as a key feature of the disease, however muscle anabolic therapies have not been successful, suggesting that treatments that target multiple aspects of the disease will be most effective. Growth differentiation factor 15 (GDF-15) is a cytokine that induces anorexia and weight loss and is associated with cachexia in cancer patients. In preclinical cancer cachexia models, GDF-15 inhibition is sufficient to normalize food intake and body weight, including skeletal muscle mass. However, it remains to be determined whether the increased skeletal muscle mass also results in restoration of muscle function. Therefore, we examined the effect of GDF-15 inhibition on muscle mass and function in mouse models of cancer cachexia in comparison with myostatin inhibition, an established muscle anabolic pathway. Methods: Cachectic mouse tumor models were established with subcutaneous implantation of tumor cell lines reported to be GDF-15-dependent; mouse renal cell carcinoma (RENCA) and human ovarian cancer (TOV-21G) cell lines. Mice were treated with anti-GDF-15 (mAB2) or anti-myostatin (RK35) monoclonal antibodies and skeletal muscle function was assessed in vivo via maximum force, maximum rate of contraction and half relax time. In the RENCA tumor model, GDF-15 inhibition fully restored body weight and skeletal muscle mass whereas myostatin inhibition showed only a modest effect. Results: Consistent with the muscle mass improvement, GDF-15 inhibition dramatically increased functional muscle endpoints compared to the partial effect of myostatin inhibition. Interestingly, in the TOV-21G tumor model GDF-15 inhibition only partially restored body weight, however skeletal muscle mass and muscle function were completely normalized. Consistent with the functional assessment, GDF-15 inhibition in the RENCA tumor model decreased the expression of several catabolic genes (i.e. Trim63, Fbxo32, Myh7 and Myh2). The GDF-15 effect is likely to be secondary to the reversal of anorexia since wildtype mice pair-fed to Fc-GDF-15-treated mice demonstrated equivalent muscle mass loss. Conclusions: Taken together these data suggest that GDF-15 inhibition holds potential as an effective therapeutic approach to alleviate multiple aspects of cachexia.

Sign in / Sign up

Export Citation Format

Share Document