scholarly journals Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy

2017 ◽  
Vol 114 (47) ◽  
pp. 12448-12453 ◽  
Author(s):  
Frederic Morvan ◽  
Jean-Michel Rondeau ◽  
Chao Zou ◽  
Giulia Minetti ◽  
Clemens Scheufler ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Growth Regulation ◽  
Muscle Growth ◽  
Muscle Loss ◽  
Binding Domains ◽  
Single Receptor ◽  
Skeletal Muscle Hypertrophy ◽  
Functional Benefit ◽  
Deficient Mice

The TGF-β family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce muscle wasting described as cachexia. Use of a soluble ActRIIB-Fc “trap,” to block myostatin pathway signaling in normal or cachectic mice leads to hypertrophy or prevention of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle growth regulation. Genetic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertrophic phenotype. Here, we describe the mode of action of bimagrumab (BYM338), as a human dual-specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels. As shown by X-ray analysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner at the critical myostatin/activin binding site, hence preventing signal transduction through either ActRII. Myostatin and the activins are capable of binding to both ActRIIA and ActRIIB, with different affinities. However, blockade of either single receptor through the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blockade upon myostatin or activin A stimulation, and this leads to only a small increase in muscle mass. Complete neutralization and maximal anabolic response are achieved only by simultaneous blockade of both receptors. These findings demonstrate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and highlight the need for blocking both receptors to achieve a strong functional benefit.

scholarly journals Paracrine and endocrine modes of myostatin action

2016 ◽  
Vol 120 (6) ◽  
pp. 592-598 ◽  
Author(s):  
Yun-Sil Lee ◽  
Thanh V. Huynh ◽  
Se-Jin Lee
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Muscle Growth ◽  
Therapeutic Strategies ◽  
Muscle Loss ◽  
Physiological Control ◽  
Critical Question ◽  
Signaling Molecule ◽  
Active Pool ◽  
Circulating Levels

Myostatin (MSTN) is a secreted signaling molecule that normally acts to limit muscle mass. In adult animals, MSTN is made almost exclusively by skeletal muscle and circulates in the blood. A critical question is whether this circulating MSTN protein can enter the active pool to regulate muscle growth or whether all of the activity of MSTN results from locally produced protein. Here, we addressed this question in mice by using a Cdx2-Cre transgene in conjunction with a conditional Mstn-flox allele to generate mice in which Mstn was targeted in a regionally restricted manner. Specifically, we generated mosaic mice in which MSTN production was eliminated in posteriorly located muscles but not in anteriorly located muscles, resulting in mice in which circulating levels of MSTN were reduced roughly by half. Analysis of posteriorly located vs. anteriorly located muscles of these mice revealed clear differential effects indicative of an important paracrine role for MSTN in regulating muscle mass. Significant, albeit more subtle, effects consistent with an endocrine mode of MSTN action were also seen in these mice. These findings have important implications not only for the understanding of the physiological control of muscle mass but also for therapeutic strategies to target MSTN to treat patients with muscle loss.

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 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 Exercise Mitigates the Loss of Muscle Mass by Attenuating the Activation of Autophagy during Severe Energy Deficit

Nutrients ◽  
2019 ◽  
Vol 11 (11) ◽  
pp. 2824 ◽  
Author(s):  
Marcos Martin-Rincon ◽  
Alberto Pérez-López ◽  
David Morales-Alamo ◽  
Ismael Perez-Suarez ◽  
Pedro de Pablos-Velasco ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Prolonged Exercise ◽  
Control Diet ◽  
Energy Deficit ◽  
Muscle Loss ◽  
Volume Changes ◽  
Autophagy Induction ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway

The loss of skeletal muscle mass with energy deficit is thought to be due to protein breakdown by the autophagy-lysosome and the ubiquitin-proteasome systems. We studied the main signaling pathways through which exercise can attenuate the loss of muscle mass during severe energy deficit (5500 kcal/day). Overweight men followed four days of caloric restriction (3.2 kcal/kg body weight day) and prolonged exercise (45 min of one-arm cranking and 8 h walking/day), and three days of control diet and restricted exercise, with an intra-subject design including biopsies from muscles submitted to distinct exercise volumes. Gene expression and signaling data indicate that the main catabolic pathway activated during severe energy deficit in skeletal muscle is the autophagy-lysosome pathway, without apparent activation of the ubiquitin-proteasome pathway. Markers of autophagy induction and flux were reduced by exercise primarily in the muscle submitted to an exceptional exercise volume. Changes in signaling are associated with those in circulating cortisol, testosterone, cortisol/testosterone ratio, insulin, BCAA, and leucine. We conclude that exercise mitigates the loss of muscle mass by attenuating autophagy activation, blunting the phosphorylation of AMPK/ULK1/Beclin1, and leading to p62/SQSTM1 accumulation. This includes the possibility of inhibiting autophagy as a mechanism to counteract muscle loss in humans under severe energy deficit.

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 Defective skeletal muscle growth in lamin A/C-deficient mice is rescued by loss of Lap2α

2013 ◽  
Vol 22 (14) ◽  
pp. 2852-2869 ◽  
Author(s):  
Tatiana V. Cohen ◽  
Viola F. Gnocchi ◽  
Jonathan E. Cohen ◽  
Aditi Phadke ◽  
Henry Liu ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Growth ◽  
Lamin A ◽  
Skeletal Muscle Growth ◽  
Deficient Mice

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 The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass

2013 ◽  
Vol 203 (2) ◽  
pp. 345-357 ◽  
Author(s):  
Catherine E. Winbanks ◽  
Justin L. Chen ◽  
Hongwei Qian ◽  
Yingying Liu ◽  
Bianca C. Bernardo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Bone Morphogenetic Protein ◽  
Signaling Pathway ◽  
Muscle Mass ◽  
Muscle Wasting ◽  
Muscle Growth ◽  
Bmp Signaling ◽  
Positive Regulator ◽  
Bmp Receptors ◽  
Morphogenetic Protein

Although the canonical transforming growth factor β signaling pathway represses skeletal muscle growth and promotes muscle wasting, a role in muscle for the parallel bone morphogenetic protein (BMP) signaling pathway has not been defined. We report, for the first time, that the BMP pathway is a positive regulator of muscle mass. Increasing the expression of BMP7 or the activity of BMP receptors in muscles induced hypertrophy that was dependent on Smad1/5-mediated activation of mTOR signaling. In agreement, we observed that BMP signaling is augmented in models of muscle growth. Importantly, stimulation of BMP signaling is essential for conservation of muscle mass after disruption of the neuromuscular junction. Inhibiting the phosphorylation of Smad1/5 exacerbated denervation-induced muscle atrophy via an HDAC4-myogenin–dependent process, whereas increased BMP–Smad1/5 activity protected muscles from denervation-induced wasting. Our studies highlight a novel role for the BMP signaling pathway in promoting muscle growth and inhibiting muscle wasting, which may have significant implications for the development of therapeutics for neuromuscular disorders.

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.

Protein Intake for Skeletal Muscle Hypertrophy with Resistance Training in Seniors

2006 ◽  
Vol 16 (4) ◽  
pp. 362-372 ◽  
Author(s):  
Ryan D. Andrews ◽  
David A. MacLean ◽  
Steven E. Riechman
Keyword(s):  
Skeletal Muscle ◽  
Muscle Mass ◽  
Lean Mass ◽  
Protein Intake ◽  
Muscle Hypertrophy ◽  
Protein Supplementation ◽  
Protein Supplement ◽  
Resistance Exercise Training ◽  
Post Exercise ◽  
Skeletal Muscle Hypertrophy

Variability in protein consumption may influence muscle mass changes induced by resistance exercise training (RET). We sought to administer a post-exercise protein supplement and determine if daily protein intake variability affected variability in muscle mass gains. Men (N = 22) and women (N = 30) ranging in age from 60 to 69 y participated in a 12-wk RET program. At each RET session, participants consumed a post-exercise drink (0.4 g/kg lean mass protein). RET resulted in significant increases in lean mass (1.1 ±1.5 kg), similar between sexes (P > 0.05). Variability in mean daily protein intake was not associated with change in lean mass (r < 0.10, P > 0.05). The group with the highest protein intake (1.35 g · kg−1 · d−1, n = 8) had similar (P > 0.05) changes in lean mass as the group with the lowest daily protein intake (0.72 g · kg−1 · d−1, n = 9). These data suggest that variability in total daily protein intake does not affect variability in lean mass gains with RET in the context of post-exercise protein supplementation.

Sign in / Sign up

Export Citation Format

Share Document