Concurrent BMP Signaling Maintenance and TGF-β Signaling Inhibition Is a Hallmark of Natural Resistance to Muscle Atrophy in the Hibernating Bear

Muscle atrophy arises from a multiplicity of physio-pathological situations and has very detrimental consequences for the whole body. Although knowledge of muscle atrophy mechanisms keeps growing, there is still no proven treatment to date. This study aimed at identifying new drivers for muscle atrophy resistance. We selected an innovative approach that compares muscle transcriptome between an original model of natural resistance to muscle atrophy, the hibernating brown bear, and a classical model of induced atrophy, the unloaded mouse. Using RNA sequencing, we identified 4415 differentially expressed genes, including 1746 up- and 2369 down-regulated genes, in bear muscles between the active versus hibernating period. We focused on the Transforming Growth Factor (TGF)-β and the Bone Morphogenetic Protein (BMP) pathways, respectively, involved in muscle mass loss and maintenance. TGF-β- and BMP-related genes were overall down- and up-regulated in the non-atrophied muscles of the hibernating bear, respectively, and the opposite occurred for the atrophied muscles of the unloaded mouse. This was further substantiated at the protein level. Our data suggest TGF-β/BMP balance is crucial for muscle mass maintenance during long-term physical inactivity in the hibernating bear. Thus, concurrent activation of the BMP pathway may potentiate TGF-β inhibiting therapies already targeted to prevent muscle atrophy.

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GDF11 promotes osteogenesis as opposed to MSTN, and follistatin, a MSTN/GDF11 inhibitor, increases muscle mass but weakens bone

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1916034117 ◽

2020 ◽

Vol 117 (9) ◽

pp. 4910-4920 ◽

Cited By ~ 3

Author(s):

Joonho Suh ◽

Na-Kyung Kim ◽

Seung-Hoon Lee ◽

Je-Hyun Eom ◽

Youngkyun Lee ◽

...

Keyword(s):

Bone Mass ◽

Muscle Mass ◽

Transforming Growth Factor ◽

Bone Fractures ◽

Muscle Growth ◽

Transforming Growth Factor Β ◽

Biochemical Properties ◽

Bmp Signaling ◽

Morphogenetic Protein ◽

Perinatal Lethality

Growth and differentiation factor 11 (GDF11) and myostatin (MSTN) are closely related transforming growth factor β (TGF-β) family members, but their biological functions are quite distinct. While MSTN has been widely shown to inhibit muscle growth, GDF11 regulates skeletal patterning and organ development during embryogenesis. Postnatal functions of GDF11, however, remain less clear and controversial. Due to the perinatal lethality ofGdf11null mice, previous studies used recombinant GDF11 protein to prove its postnatal function. However, recombinant GDF11 and MSTN proteins share nearly identical biochemical properties, and most GDF11-binding molecules have also been shown to bind MSTN, generating the possibility that the effects mediated by recombinant GDF11 protein actually reproduce the endogenous functions of MSTN. To clarify the endogenous functions of GDF11, here, we focus on genetic studies and show thatGdf11null mice, despite significantly down-regulatingMstnexpression, exhibit reduced bone mass through impaired osteoblast (OB) and chondrocyte (CH) maturations and increased osteoclastogenesis, while the opposite is observed inMstnnull mice that display enhanced bone mass. Mechanistically,Mstndeletion up-regulatesGdf11expression, which activates bone morphogenetic protein (BMP) signaling pathway to enhance osteogenesis. Also, mice overexpressing follistatin (FST), a MSTN/GDF11 inhibitor, exhibit increased muscle mass accompanied by bone fractures, unlikeMstnnull mice that display increased muscle mass without fractures, indicating that inhibition of GDF11 impairs bone strength. Together, our findings suggest that GDF11 promotes osteogenesis in contrast to MSTN, and these opposing roles of GDF11 and MSTN must be considered to avoid the detrimental effect of GDF11 inhibition when developing MSTN/GDF11 inhibitors for therapeutic purposes.

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Tail suspension is useful as a sarcopenia model in rats

Laboratory Animal Research ◽

10.1186/s42826-020-00083-9 ◽

2021 ◽

Vol 37 (1) ◽

Author(s):

Akira Nemoto ◽

Toru Goyagi

Keyword(s):

Skeletal Muscle ◽

Muscle Contraction ◽

Experimental Model ◽

Muscle Mass ◽

Muscle Atrophy ◽

Whole Body ◽

Skeletal Muscle Atrophy ◽

Enzyme Linked Immunosorbent Assay ◽

Control Group ◽

Simple Method

Abstract Background Sarcopenia promotes skeletal muscle atrophy and exhibits a high mortality rate. Its elucidation is of the highest clinical importance, but an animal experimental model remains controversial. In this study, we investigated a simple method for studying sarcopenia in rats. Results Muscle atrophy was investigated in 24-week-old, male, tail-suspended (TS), Sprague Dawley and spontaneously hypertensive rats (SHR). Age-matched SD rats were used as a control group. The skeletal muscle mass weight, muscle contraction, whole body tension (WBT), cross-sectional area (CSA), and Muscle RING finger-1 (MuRF-1) were assessed. Enzyme-linked immunosorbent assay was used to evaluate the MuRF-1 levels. Two muscles, the extensor digitorum longus and soleus muscles, were selected for representing fast and slow muscles, respectively. All data, except CSA, were analyzed by a one-way analysis of variance, whereas CSA was analyzed using the Kruskal-Wallis test. Muscle mass weight, muscle contraction, WBT, and CSA were significantly lower in the SHR (n = 7) and TS (n = 7) groups than in the control group, whereas MuRF-1 expression was dominant. Conclusions TS and SHR presented sarcopenic phenotypes in terms of muscle mass, muscle contraction and CSA. TS is a useful technique for providing muscle mass atrophy and weakness in an experimental model of sarcopenia in rats.

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Increasing autophagy does not affect neurogenic muscle atrophy

European Journal of Translational Myology ◽

10.4081/ejtm.2018.7687 ◽

2018 ◽

Vol 28 (3) ◽

Cited By ~ 5

Author(s):

Eva Pigna ◽

Krizia Sanna ◽

Dario Coletti ◽

Zhenlin Li ◽

Ara Parlakian ◽

...

Keyword(s):

Muscle Mass ◽

Muscle Atrophy ◽

Ubiquitin Proteasome System ◽

Autophagic Flux ◽

Molecular Pathways ◽

Muscle Loss ◽

Relative Contribution ◽

Ubiquitin Proteasome ◽

Muscle Mass Loss ◽

Kinetics Of

Physiological autophagy plays a crucial role in the regulation of muscle mass and metabolism, while the excessive induction or the inhibition of the autophagic flux contributes to the progression of several diseases. Autophagy can be activated by different stimuli, including cancer, exercise, caloric restriction and denervation. The latter leads to muscle atrophy through the activation of catabolic pathways, i.e. the ubiquitin-proteasome system and autophagy. However, the kinetics of autophagy activation and the upstream molecular pathways in denervated skeletal muscle have not been reported yet. In this study, we characterized the kinetics of autophagic induction, quickly triggered by denervation, and report the Akt/mTOR axis activation. Besides, with the aim to assess the relative contribution of autophagy in neurogenic muscle atrophy, we triggered autophagy with different stimuli along with denervation, and observed that four week-long autophagic induction, by either intermitted fasting or rapamycin treatment, did not significantly affect muscle mass loss. We conclude that: i) autophagy does not play a major role in inducing muscle loss following denervation; ii) nonetheless, autophagy may have a regulatory role in denervation induced muscle atrophy, since it is significantly upregulated as early as eight hours after denervation; iii) Akt/mTOR axis, AMPK and FoxO3a are activated consistently with the progression of muscle atrophy, further highlighting the complexity of the signaling response to the atrophying stimulus deriving from denervation.

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Nutritional strategies to counteract muscle atrophy caused by disuse and to improve recovery

Nutrition Research Reviews ◽

10.1017/s0954422413000115 ◽

2013 ◽

Vol 26 (2) ◽

pp. 149-165 ◽

Cited By ~ 35

Author(s):

Hugues Magne ◽

Isabelle Savary-Auzeloux ◽

Didier Rémond ◽

Dominique Dardevet

Keyword(s):

Mass Loss ◽

Muscle Mass ◽

Muscle Atrophy ◽

Whey Proteins ◽

Leucine Supplementation ◽

Positive Effects ◽

Muscle Disuse ◽

Muscle Mass Loss ◽

Nutritional Strategies ◽

Mass Recovery

Periods of immobilisation are often associated with pathologies and/or ageing. These periods of muscle disuse induce muscle atrophy which could worsen the pathology or elderly frailty. If muscle mass loss has positive effects in the short term, a sustained/uncontrolled muscle mass loss is deleterious for health. Muscle mass recovery following immobilisation-induced atrophy could be critical, particularly when it is uncompleted as observed during ageing. Exercise, the best way to recover muscle mass, is not always applicable. So, other approaches such as nutritional strategies are needed to limit muscle wasting and to improve muscle mass recovery in such situations. The present review discusses mechanisms involved in muscle atrophy following disuse and during recovery and emphasises the effect of age in these mechanisms. In addition, the efficiency of nutritional strategies proposed to limit muscle mass loss during disuse and to improve protein gain during recovery (leucine supplementation, whey proteins, antioxidants and anti-inflammatory compounds, energy intake) is also discussed.

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The Interactivity between TGFβ and BMP Signaling in Organogenesis, Fibrosis, and Cancer

Cells ◽

10.3390/cells8101130 ◽

2019 ◽

Vol 8 (10) ◽

pp. 1130 ◽

Cited By ~ 18

Author(s):

Francesco Dituri ◽

Carla Cossu ◽

Serena Mancarella ◽

Gianluigi Giannelli

Keyword(s):

Transforming Growth Factor Beta ◽

Transforming Growth Factor ◽

Bmp Signaling ◽

Tissue Homeostasis ◽

Adult Tissue ◽

Developmental Defects ◽

Cellular Processes ◽

Bmp Pathway ◽

Growth Factor Beta ◽

Multiple Signaling

The Transforming Growth Factor beta (TGFβ) and Bone Morphogenic Protein (BMP) pathways intersect at multiple signaling hubs and cooperatively or counteractively participate to bring about cellular processes which are critical not only for tissue morphogenesis and organogenesis during development, but also for adult tissue homeostasis. The proper functioning of the TGFβ/BMP pathway depends on its communication with other signaling pathways and any deregulation leads to developmental defects or diseases, including fibrosis and cancer. In this review we explore the cellular and physio-pathological contexts in which the synergism or antagonism between the TGFβ and BMP pathways are crucial determinants for the normal developmental processes, as well as the progression of fibrosis and malignancies.

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Extracellular BMP Antagonists, Multifaceted Orchestrators in the Tumor and Its Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms21113888 ◽

2020 ◽

Vol 21 (11) ◽

pp. 3888

Author(s):

Sarah Ouahoud ◽

James C.H. Hardwick ◽

Lukas J.A.C. Hawinkels

Keyword(s):

Cancer Progression ◽

Bone Morphogenetic Proteins ◽

Transforming Growth Factor ◽

Transforming Growth Factor Β ◽

Bmp Signaling ◽

Biological Processes ◽

Adult Tissue ◽

Aberrant Expression ◽

Bmp Pathway ◽

Bmp Antagonists

The bone morphogenetic proteins (BMPs), a subgroup of the transforming growth factor-β (TGF-β) superfamily, are involved in multiple biological processes such as embryonic development and maintenance of adult tissue homeostasis. The importance of a functional BMP pathway is underlined by various diseases, including cancer, which can arise as a consequence of dysregulated BMP signaling. Mutations in crucial elements of this signaling pathway, such as receptors, have been reported to disrupt BMP signaling. Next to that, aberrant expression of BMP antagonists could also contribute to abrogated signaling. In this review we set out to highlight how BMP antagonists affect not only the cancer cells, but also the other cells present in the microenvironment to influence cancer progression.

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Inhibition of apelin expression by BMP signaling in endothelial cells

AJP Cell Physiology ◽

10.1152/ajpcell.00168.2012 ◽

2012 ◽

Vol 303 (11) ◽

pp. C1139-C1145 ◽

Cited By ~ 27

Author(s):

Odette Poirier ◽

Mariana Ciumas ◽

Mélanie Eyries ◽

Kevin Montagne ◽

Sophie Nadaud ◽

...

Keyword(s):

Endothelial Cells ◽

Transforming Growth Factor ◽

Vascular Diseases ◽

Transforming Growth Factor Β ◽

Inhibitory Effect ◽

Bmp Signaling ◽

Gene Encoding ◽

Major Pathway ◽

Bmp Pathway ◽

Microvascular Cells

The transforming growth factor-β/bone morphogenic protein (BMP) system is a major pathway for angiogenesis and is involved in hereditary vascular diseases. Here we report that the gene encoding the vasoactive and vascular cell growth-regulating peptide apelin is a target of the BMP pathway. We demonstrate that apelin expression is strongly downregulated by BMP in an endothelial cell line as well as in lung endothelial microvascular cells. We show that BMP signals through the BMPR2-SMAD pathway to downregulate apelin expression and that a transcriptional direct and indirect mechanism is required. The BMP-induced downregulation of apelin expression was found to be critical for hypoxia-induced growth of endothelial cells, because the growth inhibitory effect of BMP in this condition is suppressed by enforced expression of apelin. Thus, we describe an important link between a signaling pathway involved in angiogenesis and vascular diseases and a peptide regulating vascular homeostasis.

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Skeletal muscle response to spaceflight, whole body suspension, and recovery in rats

Journal of Applied Physiology ◽

10.1152/jappl.1990.69.6.2248 ◽

1990 ◽

Vol 69 (6) ◽

pp. 2248-2253 ◽

Cited By ~ 53

Author(s):

X. J. Musacchia ◽

J. M. Steffen ◽

R. D. Fell ◽

M. J. Dombrowski

Keyword(s):

Muscle Mass ◽

Muscle Metabolism ◽

Capillary Density ◽

Whole Body ◽

Sprague Dawley ◽

Cross Sectional ◽

Muscle Plasticity ◽

Sprague Dawley Rats ◽

Muscle Mass Loss ◽

Fast Twitch

Comparisons of soleus and extensor digitorum longus (EDL) muscles from male Sprague-Dawley rats (350-400 g) after 7 days of weightlessness, 7 and 14 days of whole body suspension (WBS), and 7 days of recovery from WBS and from vivarium controls were made. Muscle mass loss of approximately 30% was observed in soleus after 7 and 14 days of WBS. Measurement of slow- and fast-twitch fibers showed significant alterations. Reductions in cross-sectional areas and increases in fiber densities in soleus after spaceflight and WBS were related to previous findings of muscle atrophy during unloading. Capillary density also showed a marked increase with unloading. Seven days of weightlessness were sufficient to effect a 20 and 15% loss in absolute muscle mass in soleus and EDL, respectively. However, the antigravity soleus was more responsive in terms of cross-sectional area reductions. After 7 days of recovery from WBS, with normal ambulatory loading, the parameters studied showed a reversal to control levels. Muscle plasticity, in terms of fiber and capillary responses, indicated differences in responses in the two types of muscles and further amplified that antigravity posture muscles are highly susceptible to unloading. Studies of recovery from spaceflight for both muscle metabolism and microvascular modifications are further justified.

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The BMP Pathway and Its Inhibitors in the Skeleton

Physiological Reviews ◽

10.1152/physrev.00028.2017 ◽

2018 ◽

Vol 98 (4) ◽

pp. 2431-2452 ◽

Cited By ~ 37

Author(s):

Jonathan W. Lowery ◽

Vicki Rosen

Keyword(s):

Gene Regulatory Network ◽

Regulatory Network ◽

Transforming Growth Factor ◽

Bone Development ◽

Transforming Growth Factor Β ◽

Bmp Signaling ◽

Comprehensive Overview ◽

Organ Systems ◽

Bmp Pathway ◽

Gene Regulatory

Bone morphogenetic proteins (BMPs) constitute the largest subdivision of the transforming growth factor-β family of ligands. BMPs exhibit widespread utility and pleiotropic, context-dependent effects, and the strength and duration of BMP pathway signaling is tightly regulated at numerous levels via mechanisms operating both inside and outside the cell. Defects in the BMP pathway or its regulation underlie multiple human diseases of different organ systems. Yet much remains to be discovered about the BMP pathway in its original context, i.e., the skeleton. In this review, we provide a comprehensive overview of the intricacies of the BMP pathway and its inhibitors in bone development, homeostasis, and disease. We frame the content of the review around major unanswered questions for which incomplete evidence is available. First, we consider the gene regulatory network downstream of BMP signaling in osteoblastogenesis. Next, we examine why some BMP ligands are more osteogenic than others and what factors limit BMP signaling during osteoblastogenesis. Then we consider whether specific BMP pathway components are required for normal skeletal development, and if the pathway exerts endogenous effects in the aging skeleton. Finally, we propose two major areas of need of future study by the field: greater resolution of the gene regulatory network downstream of BMP signaling in the skeleton, and an expanded repertoire of reagents to reliably and specifically inhibit individual BMP pathway components.

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Generic and context-dependent gene modulations duringHydrawhole body regeneration

10.1101/587147 ◽

2019 ◽

Cited By ~ 6

Author(s):

Yvan Wenger ◽

Wanda Buzgariu ◽

Chrystelle Perruchoud ◽

Gregory Loichot ◽

Brigitte Galliot

Keyword(s):

Classical Model ◽

Expression Patterns ◽

Bmp Signaling ◽

Whole Body ◽

Basal Region ◽

Web Interface ◽

Regenerative Processes ◽

Ectopic Activation ◽

Gene Regulations

AbstractThe cnidarianHydrais a classical model of whole-body regeneration. Historically,Hydraapical regeneration has received more attention than its basal counterpart, most studies considering these two regenerative processes independently. We present here a transcriptome-wide comparative analysis of apical and basal regeneration after decapitation and mid-gastric bisection, augmented with a characterization of positional and cell-type expression patterns in non-regenerating animals. The profiles of 25’637Hydratranscripts are available on HydrATLAS (https://hydratlas.unige.ch), a web interface allowing a convenient access to each transcript profile. These data indicate that generic impulse-type modulations occur during the first four hours post-amputation, consistent with a similar integration of injury-related cues on both sides of the amputation plane. Initial divergences in gene regulations are observed in regenerating tips between four and eight hours post-amputation, followed by a dramatic transcriptomic reprogramming between eight and 16 hours when regulations become sustained. As expected, central components of apical patterning,Wnt3andHyBra1, are among the earliest genes up-regulated during apical regeneration. During early basal regeneration, a BMP signaling ligand (BMP5-8c) and a potential BMP inhibitor (NBL1)are up-regulated, suggesting that BMP signaling is involved in the basal organizer, as supported by higher levels of phosphorylated Smad in the basal region and by the LiCl-induced extension ofNBL1expression. By contrast, upon ectopic activation of Wnt/β-catenin signaling,NBL1is no longer expressed, basal differentiation is not maintained and basal regeneration is abolished. A tight cross-talk between Wnt/β-catenin apically and BMP signaling basally appears necessary for maintaining and regeneratingHydraanatomy.

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