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Role of TGF-β signaling in inherited and acquired myopathies

Tyesha N Burks, Ronald D Cohn

Skeletal Muscle · 2011 · Review

doi:10.1186/2044-5040-1-19

Abstract

The transforming growth factor-beta (TGF-β) superfamily consists of a variety of cytokines expressed in many different cell types including skeletal muscle. Members of this superfamily that are of particular importance in skeletal muscle are TGF-β1, mitogen-activated protein kinases (MAPKs), and myostatin. These signaling molecules play important roles in skeletal muscle homeostasis and in a variety of inherited and acquired neuromuscular disorders. Expression of these molecules is linked to normal processes in skeletal muscle such as growth, differentiation, regeneration, and stress response. However, chronic elevation of TGF-β1, MAPKs, and myostatin is linked to various features of muscle pathology, including impaired regeneration and atrophy. In this review, we focus on the aberrant signaling of TGF-β in various disorders such as Marfan syndrome, muscular dystrophies, sarcopenia, and critical illness myopathy. We also discuss how the inhibition of several members of the TGF-β signaling pathway has been implicated in ameliorating disease phenotypes, opening up novel therapeutic avenues for a large group of neuromuscular disorders.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

The transforming growth factor-beta (TGF-β) superfamily plays a crucial role in normal physiology and pathogenesis in a number of tissues. It is important to emphasize that downstream effects of this signaling cascade are often tissue-specific, thereby dictating which target genes will be activated in response to the transduction signal. Given its multifaceted effects in different tissues, deregulation of TGF-β signaling cascades can lead to a multitude of developmental defects and/or disease. Several members of the TGF-β family have been shown to play important roles in regulating muscle growth and atrophy. The most extensively characterized ligands, in terms of the effects on skeletal muscle, are TGF-β1, mitogen-activated protein kinases (MAPKs), and myostatin. In this review, we focus on these signaling molecules in normal homeostasis and pathological conditions affecting skeletal muscle and describe the therapeutic avenues that have recently been explored to target the TGF-β signaling cascade.

Overview of the TGF-β superfamily signaling cascade

The TGF-β superfamily of cytokines consists of a variety of signaling molecules including isoforms of TGF-β (1 to 3), bone morphogenic proteins (BMPs 1 to 20), growth and differentiation factors (GDFs), activins (A and B), inhibins (A and B), nodal, leftys (1 and 2), and Mullerian inhibiting substance. They are generally divided into two branches defined by the utilization of receptor Smads (R-Smads): the TGF-β branch, consisting of TGF-β, activin, Nodal, and myostatin (GDF-8), signals through R-Smads 2 and 3 and the BMP branch, consisting of BMPs and other GDFs, signals through R-Smads 1, 5 and 8. This superfamily is known to be involved in embryonic development, adult tissue homeostasis, and disease pathogenesis. Specifically, it has been shown to control proliferation, differentiation, apoptosis, migration, extracellular matrix (ECM) remodeling, immune functions, and tumor invasion/metastasis.

TGF-β1 is synthesized as a precursor that is cleaved intracellularly into an inactive complex consisting of the mature TGF-β1 non-covalently bound to the portion of the precursor peptide termed the latency-associated peptide (LAP). This inactive TGF-β1-LAP complex forms a larger complex with latent transforming growth factor-binding proteins (LTBPs), which directly bind and release TGF-β1 from the ECM. Specifically, LTBP-4 sequesters and regulates the availability of TGF-β1 to bind with its receptor. Cleavage of TGF-β1 from the latent complex is achieved through the action of proteases such as plasmin, thrombin, plasma transglutaminases, or endoglycosylases, or through the physical interaction of LAPs with other proteins. Activation occurs extracellularly, and once TGF-β1 is released, it is able to interact with and complex its type I (usually TβR-II) and type II (usually activin receptor-like kinase (ALK) 5) receptors. The constitutively active type II receptor phosphorylates and activates the type I receptor, which in turn directly phosphorylates Smad2 and/or Smad3 (which are recruited by adaptor proteins) to initiate signal transduction through the canonical cascades. Once R-Smad has been phosphorylated, it forms a complex with the common mediator Smad (co-Smad), Smad4, which translocates to the nucleus, where it directly binds defined elements on the DNA. Adding to the regulation are the inhibitory Smads 6 and 7. Smad7 is involved in both branches and competes with R-Smads for interaction with the type I receptor, whereas Smad6 only participates in the BMP pathway and competes with Smad4 for binding to Smad1 (Figure 1).

TGF-β1 can also signal via induction of non-canonical pathways including MAPK. The MAPK family consists of isoforms of extracellular signal-regulated kinases (ERKs) (1 and 2), c-Jun N-terminal kinase (JNKs) (1to 3), and p38 (α, β, γ and δ). The mechanisms of MAPK activation by TGF-β1 and the subsequent biological consequences are cell-type-specific. Generally in the non-Smad pathway, the type I receptor associates with the adaptor proteins, Shc and tumor necrosis factor receptor-associated factor (TRAF) 6, for the activation of Ras and TGF-β-activated kinase (TAK) 1 and subsequently, the ERK and p38/JNK pathways, respectively. However, MAPK may also modulate TGF-β1-induced Smad signals and phosphorylate Smad proteins independent of TGF-β1, providing evidence for crosstalk between canonical and non-canonical TGF-β pathways (Figure 1).

Myostatin (MSTN), predominantly expressed in skeletal muscle, also signals through the TGF-β branch. It is synthesized as a precursor protein that undergoes processing by furin proteases to generate a propeptide. After proteolytic processing, however, the biologically active MSTN remains bound non-covalently to the propeptide, and in this complex, the propeptide maintains its inactive, latent state. MSTN also seems to be regulated extracellularly by other binding proteins: follistatin, follistatin-related gene (FLRG) protein, and growth and differentiation factor-associated serum protein (GASP) 1. When not bound to its propeptide or binding proteins, active MSTN is able to signal to target cells by binding to the activin type II receptors, ActRIIA or ActRIIB. The activation of the type I receptor (usually ALK5 and to a lesser extent ALK4) leads to the phosphorylation of R-Smads 2 and 3. More recently, it has been shown that MSTN is also able to induce the activation of the MAPK signaling pathway in Smad-dependent and -independent mechanisms, and to inhibit the Akt/TORC1/p70S6K signaling pathway (Figure 1). For a more extensive summary of MSTN, see.

Physiological role of TGF-β signaling in skeletal muscle

TGF-β1 is expressed during myogenesis, and its spatial and temporal expression in the developing connective tissue is correlated with the fiber-type composition of the surrounding myotubes. Myotubes formed before the expression of TGF-β1 develop into slow fibers, whereas fast fibers form when myoblasts are adjacent to connective tissue expressing TGF-β1. TGF-β1 has been shown to inhibit the differentiation of fetal myoblasts but does not affect embryonic myoblasts. In mature adult muscle, TGF-β negatively affects skeletal muscle regeneration by inhibiting satellite cell proliferation, myofiber fusion, and expression of some muscle-specific genes. Furthermore, TGF-β1 induces the transformation of myogenic cells into fibrotic cells after injury.

Not much is known about the role of the different MAPKs in embryogenesis; although, they have been shown to play a role in myogenesis and regeneration. p38 is speculated to regulate regeneration through the activation of p21, a cyclin-dependent inhibitor that causes irreversible withdrawal from the cell cycle (necessary for the differentiation of myoblasts) and through interactions with Pax7, myogenic regulatory factors, and myocyte enhancer factors. JNK is proposed to inhibit myogenesis, and ERK may have multiple roles: preventing the initiation of myogenesis, enhancing myoblast proliferation during the acute stages, and repressing muscle-specific gene expression and myoblast differentiation, if expression is sustained. Generally, in mature muscle, MAPKs mediate the transduction of diverse external stress stimuli into intracellular signals that regulate adaptive cellular responses such as proliferation, differentiation, self-renewal, and survival in diseased and healthy states. For example, MAPK levels are modulated during exercise and aging as a stress response.

Myostatin is expressed in developing skeletal muscle throughout embryogenesis and has been shown to be a negative regulator of adult skeletal muscle mass by acting on different mechanisms. Genetic studies in mice, cattle, sheep, dogs, chickens, and humans have all shown that myostatin normally functions to limit muscle mass. In mice, targeted ablation of the Mstn gene causes a doubling of skeletal muscle mass throughout the body, as a result of a combination of muscle fiber hyperplasia and hypertrophy. Moreover, postnatal inhibition of myostatin signaling through the delivery of propeptides, neutralizing antibodies, antisense RNA, inhibitory proteins, and soluble ActRIIB has been shown to induce significant muscle growth when administered to mice of different ages, demonstrating the importance of this signaling pathway in regulating muscle homeostasis.

TGF-β signaling and skeletal-muscle repair

After skeletal muscle injury, a well-coordinated repair process occurs. This process includes the release of growth factors and cytokines and the migration and proliferation of macrophages and fibroblasts that increase the production of ECM components; these components are degraded as normal regeneration occurs. The inflammatory response serves to clear myofiber debris and modulate regeneration. The formation of new myofibers begins with the activation of satellite cells, followed by proliferation, differentiation, and fusion of myocytes (Figure 2).

TGF-β1, a potent regulator of tissue wound healing and fibrosis, is physiologically upregulated in regenerating skeletal muscle after injury and exercise and is thought to participate in a transient inflammatory response to muscle damage. Persistent exposure to the inflammatory response leads to an altered ECM and increased levels of growth factors and cytokines, including TGF-β1, which contribute to the formation of fibrotic tissue. Therefore, TGF-β1 is one of the major factors promoting the transformation of myoblasts into fibrotic tissue after injury. Furthermore, increased levels of TGF-β1 inhibit satellite cell activation and impair myocyte differentiation (Figure 2). Interestingly, reducing the levels of TGF-β1 in various physiological and pathological conditions associated with muscle homeostasis and regeneration has proven to be beneficial for several myopathic conditions (Table 1).

Myostatin also impairs skeletal muscle regeneration. It is proposed to hinder the chemotaxis of macrophages and myoblasts, while simultaneously activating and attracting fibroblasts to the site of injury. Once fibroblasts are within the environment of the injured muscle, they express MSTN and differentiate into myofibroblasts, a process that in turn accelerates the deposition of collagen and connective tissue, ultimately promoting the formation of tissue fibrosis. Furthermore, myostatin inhibits the activation, differentiation, and self-renewal of satellite cells and the expression of the muscle regulatory factors crucial for the regeneration and differentiation process of myofibers (Figure 2). Inhibiting MSTN in various myopathic conditions has yielded mixed results, depending on the disease model and mechanism of inhibition (Table 2).

Role of TGF-β signaling in disease pathogenesis of inherited myopathies

Dysregulation of TGF-β signaling has been implicated in various pathological conditions affecting skeletal muscle, both inherited and acquired. Inherited conditions can be progressive, and therefore, there are unique phenotypic characteristics that may require different modes of intervention. Indeed, increased levels of TGF-β, MAPK, and/or MSTN have been associated with spinal muscular atrophy and Kennedy disease, and inhibition of MSTN improves familial amyotrophic lateral sclerosis (ALS), but this review focuses on altered signaling in the pathogenesis of Marfan syndrome (MFS) and the muscular dystrophies.

MFS is an autosomal dominant systemic disorder of connective tissue, caused by mutations in FBN1, the gene encoding the ECM protein, fibrillin-1. A large subset of patients exhibit a significant decrease in muscle mass, often associated with hypotonia, particularly during early childhood, and experience a life-long inability to increase muscle mass despite physical exercise. Histological analyses of skeletal muscle from fibrillin-1-deficient mice and patients with MFS demonstrated a decrease in the number and size of myofibers, accompanied by an increase in fibrosis, fat deposition, and the number of split fibers. Further molecular analyses revealed that an increase in TGF-β signaling was indeed responsible for the abnormal muscle phenotype and the impaired ability to regenerate muscle in response to injury. Interestingly, when TGF-β signaling was blunted via treatment with a TGF-β neutralizing antibody or losartan, mice deficient in fibrillin-1 exhibited normal muscle architecture and regeneration capabilities.

'Muscular dystrophy' (MD) is a term used to describe a group of over 30 inherited disorders characterized by variable progressive muscle weakness and wasting. Genetic mutations in genes encoding proteins spanning every subcellular aspect of the myofiber have been described. There are currently no unifying hypotheses integrating all forms of MDs, but various lines of evidence suggest that repeated cycles of degeneration and regeneration may eventually impair the ability of satellite cells to repopulate damaged muscle. Once muscle regeneration declines, there is often an accumulation of inflammation and fibrosis, which results in an abundance of growth factors and cytokines including TGF-β1, as stated above. Similarly, the levels of decorin and biglycan, components of the ECM that interact with cytokines such as TGF-β1, as well as modulations of MAPK and myostatin signaling, are altered in various forms of muscular dystrophies including congenital MD, Emery-Dreifuss MD (EDMD) and Becker MD. This review will elaborate on findings in Duchenne and limb-girdle MDs.

Duchenne muscular dystrophy (DMD) is an X-linked disorder characterized by a complete lack of dystrophin, which renders the myofiber membrane unstable. Inflammation is thought to precede the overexpression of TGF-β1 and actual muscle wasting. Additionally, other factors including ECM components, immune system components, osteopontin, and fibrinogen are increased and have been linked to fibrosis in patients and animal models of DMD. Furthermore, increased levels of the MAPKs ERK1/2, JNK1, and p38 have also been suggested to play a role in the pathogenesis of the skeletal and cardiac muscle phenotype in animal models of DMD. Insight into the different factors contributing to the fibrosis accompanying DMD has led to various mechanisms to improve the phenotype observed in cardiac and skeletal (diaphragm and limb) muscles (Table 1 and 2).

Limb-girdle muscular dystrophy (LGMD) describes a group of disorders primarily affecting the shoulder and pelvic girdle muscles, which have both autosomal dominant and recessive inheritance, and involve a variety of proteins including sarcoglycans, dysferlin, and caveolin. Studies in a Drosophila model of LGMD with γ/δ-sarcoglycan deficiency have shown that partial reduction of the Drosophila genes homologous to Smads 2/3, Smads 1/5/7, and Smad4 improved muscle function, as shown by increased climbing ability of the flies. Similarly, reducing the levels of the homologue for Smads 2/3 and Smad4 improved the heart tube phenotype. Not only has this research provided a novel animal model for studying dystrophic disease processes, but the results also indicate that targeting the R-Smads and co-Smad may be of therapeutic interest. Furthermore, genetic manipulation of LTBP-4, a latent TGF-β binding protein discussed above, affected the severity of a mouse model of sarcoglycan-deficient LGMD2C, providing evidence for an important genetic modifier of MD. An insertion in the LTBP4 gene reduced proteolysis and Smad signaling. Thus, targeting the latent complex of TGF-β1 opens up yet another therapeutic avenue for inhibiting this cytokine in various conditions affecting skeletal muscle.

Acquired myopathies implicating aberrant TGF-β signaling in disease progression

Alterations in the expression of the TGF-β signaling cascades have also been linked to acquired forms of myopathies. Muscle atrophy caused by hypoxia, microgravity exposure, starvation, acute daily psychological stress, various models of disuse, cancer, sporadic ALS, HIV, and glucocorticoid steroids is associated with increased activation of MAPK, TGF-β1, and/or MSTN. However, in this paper, we focus on sarcopenia and critical illness myopathy (CIM).

Sarcopenia refers to the physiological age-related loss of skeletal muscle mass and function. Several changes occur with age, including a decrease in myofiber size and number and diminished ability of satellite cells to activate and proliferate in response to injury, leading to impaired muscle remodeling. The molecular mechanisms underlying sarcopenia are largely unknown. However, alterations in the canonical and non-canonical TGF-β signaling pathways have been shown to play a role in the pathogenesis of sarcopenia. Studies in elderly men have demonstrated an increase in MAPK at baseline, suggesting that aging skeletal muscle is functioning under 'stress-like' conditions at rest. However, a different study conducted in mice and humans found an age-related decrease in ERK signaling in skeletal muscle and satellite cells, suggesting a contribution to the impaired regeneration. Clearly, more in-depth studies are necessary to characterize the role of MAPK signaling in aging. Additionally, alterations in the canonical TGF-β pathway include an increase in circulating TGF-β1 levels and pSmad3, which contributes to the enrichment of connective tissue within the ECM, creating an environment that interferes with satellite cell activation and proliferation and subsequent remodeling. Other studies have shown an upregulation of MSTN and that inhibition of MSTN results in an increase in muscle mass, function, and regeneration in sarcopenic mice, suggesting an important role for this protein in the process of age-related loss of muscle mass (Table 2).

CIM is characterized by generalized progressive muscle weakness and atrophy, occurring in critically ill patients who are hospitalized in the intensive care unit. There are several factors thought to contribute to the loss of muscle mass in CIM, including immobilization, systemic inflammation, high dose steroids, and other toxins. The precise molecular mechanisms underlying CIM are unknown; however, constitutively active members of the canonical and non-canonical TGF-β signaling pathways may contribute to the muscle phenotype. In fact, atrophic fibers with apoptotic features express TGF-β ligands and receptors, p38, and downstream effectors of pJNK. It is therefore tempting to speculate that TGF-β inhibition may slow or halt the progression of CIM.

Therapeutic inhibition of TGF-β signaling

Aberrant TGF-β signaling has an important role in inherited and acquired myopathies. Therefore, research has been aimed at identifying compounds that can attenuate the increased signaling of TGF-β1, MSTN, and/or MAPK levels in order to improve disease phenotypes.

Several compounds have been shown to reduce the levels of TGF-β1 in myopathies. These include FDA-approved medications with other primary clinical uses, anti-fibrotic agents, TGF-β neutralizing antibodies, and TGF-β receptor blockers. Most yielded favorable results, but there are some conditions in which blunting TGF-β signaling was not beneficial. Table 1 provides a comprehensive overview of existing agents targeting TGF-β signaling in specific disease models.

Losartan is a widely studied, FDA-approved drug commonly used in the treatment of hypertension. Its ability to attenuate TGF-β signaling in chronic renal disease, cardiomyopathies, and MFS made it an appealing molecule in the treatment of myopathies associated with increased TGF-β signaling. Long-term administration of losartan to dystrophin-negative mdx mice attenuated TGF-β signaling, decreased skeletal muscle fibrosis, and improved muscle regeneration and in vitro and in vivo function. Furthermore, long-term administration of losartan, in conjunction with exercise, in mdx mice improved the cardiac muscle function and decreased fibrosis in the cardiac, diaphragm, and limb muscles but did not improve limb muscle function. Other mechanisms of TGF-β inhibition have also yielded favorable results in the treatment of DMD and other conditions (Table 1).

Furthermore, recent experimental evidence has identified novel therapeutic targets in the TGF-β pathway. Molecules involved upstream (LTBP-4) and downstream (R-Smads and co-Smad) have been shown to modulate disease severity. It is important to emphasize that LTBP-4 is a specific target for TGF-β1, whereas Smad molecules incorporate a variety of different pathways, which could potentially lead to a number of adverse effects if they were therapeutically modified (Figure 1). Moreover, osteopontin, an inflammatory regulator that also modulates TGF-β1, has recently been shown to be upregulated during muscle regeneration and in DMD. Lack of osteopontin in mdx mice improved fibrotic tissue formation and muscle function, making osteopontin a potential therapeutic target.

In addition to altering TGF-β1 signaling, a number of compounds have been shown to inhibit myostatin signaling. Numerous studies breeding myostatin-null mice to several mouse models of inherited and acquired myopathies have shown various beneficial and non-beneficial effects. Interestingly, several studies on myostatin-null mice alone have shown that despite an increase in muscle fiber size, there is no increase in specific force, which is probably due to a disturbance in mitochondrial metabolism. Furthermore, myostatin-null mice have also been reported to have brittle tendons, which may contribute to the decrease in specific force. However, it is important to emphasize that these studies were performed in mice with a complete lack of myostatin during the development of skeletal muscle. Thus, caution is needed when extrapolating the findings obtained from myostatin-null mice to the various compounds targeting myostatin signaling postnatally.

There are several pharmacological compounds that inhibit MSTN postnatally: MSTN propeptide, MSTN peptide, inhibitory proteins (follistatin), MSTN neutralizing antibodies, histone deacetylase inhibitors, and soluble ActRIIB. These techniques have been used in various disease models, and a detailed overview is presented in Table 2.

The soluble receptor, ActRIIB, is currently being used in multiple clinical trials and has been explored in various animal models including a model of DMD. It is important to note that targeting ActRIIB could lead to adverse side effects, because its expression is not limited to skeletal muscle and because other members of the TGF-β superfamily besides myostatin bind to it. Furthermore, myostatin can also signal through another receptor, ActRIIA, but with lower affinity.

Preclinical trials with soluble ActRIIB in mdx mice have shown that short-term (3 months) intraperitoneal administration increased skeletal muscle mass and in vitro function and caused a decrease in creatine kinase levels. Adeno-associated virus (AAV)-mediated gene transfer of a soluble form of the extracellular domain of the ActRIIB to the liver provided similar results after 3.5 months, but no changes to cardiac muscle mass were seen. However, long-term (11 months) myostatin inhibition using a recombinant AAV to overexpress myostatin propeptide in mdx mice did not reduce the amount of fibrosis in the diaphragm, but caused cardiac hypertrophy and impaired function in a dose-dependent manner. These results indicate that all modes of myostatin inhibition may not be beneficial.

Similar to TGF-β1 and MSTN, perturbations of MAPK signaling have been documented in several myopathies, but not many studies exist examining the effects of inhibition on disease progression. Some evidence suggest that a reduction in JNK and ERK signaling might be beneficial in DMD and cachexia, respectively, but further studies are needed to elaborate on these initial findings. Furthermore, a number of studies have shown that inhibition of the MAPK pathway is beneficial for the cardiomyopathic phenotype of various muscular dystrophies. Specifically, it has been shown that blunting ERK or JNK before and after onset of EDMD results in less cardiac fibrosis and an overall improved function. Thus, this is a potential area of interest in designing future pharmacological compounds, because of the potential benefits and current lack of FDA-approved MAPK inhibitors.

Conclusions

Increased activity of the TGF-β superfamily plays an important role in the pathogenesis of both inherited and acquired forms of neuromuscular disorders. These alterations cause an unfavorable environment for muscle regeneration and promote an increase in fibrotic tissue formation (Figure 2). Future studies will need to address the precise timeline of alterations in TGF-β signaling in various disease processes in order to establish the optimal therapeutic intervention. A number of drugs (Table 1; Table 2) are close to or currently in clinical trials. These and future clinical trials will need to establish the safety and efficacy of these drugs and address whether certain clinical conditions may benefit from a multi-targeted approach.

Competing interests

The authors declare that they have no competing interests.

Authors' contributions

TNB designed the study and drafted the manuscript. RDC drafted the manuscript. All authors read and approved the final manuscript.

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    Zhiliang G Dahai Z Ning L Hui L Xuemei D Changxin W The single nucleotide polymorphisms of the chicken myostatin gene are associated with skeletal muscle and adipose growthSci China C Life Sci2004 472530

    Not in our library10.1360/02yc0201

  38. 38.

    Shelton GD Engvall E Gross muscle hypertrophy in whippet dogs is caused by a mutation in the myostatin geneNeuromuscul Disord2007 17721722

    Not in our library10.1016/j.nmd.2007.06.008

  39. 39.
    A Mutation in the Myostatin Gene Increases Muscle Mass and Enhances Racing Performance in Heterozygote Dogs · 2007
    No notice
  40. 40.

    Clop A Marcq F Takeda H Pirottin D Tordoir X Bibe B Bouix J Caiment F Elsen JM Eychenne F A mutation creating a potential illegitimate microRNA target site in the myostatin gene affects muscularity in sheepNat Genet2006 38813818

    Not in our library10.1038/ng1810

  41. 41.

    Whittemore LA Song K Li X Aghajanian J Davies M Girgenrath S Hill JJ Jalenak M Kelley P Knight A Inhibition of myostatin in adult mice increases skeletal muscle mass and strengthBiochem Biophys Res Commun2003 300965971

    Not in our library10.1016/s0006-291x(02)02953-4

  42. 42.

    Haidet AM Rizo L Handy C Umapathi P Eagle A Shilling C Boue D Martin PT Sahenk Z Mendell JR Kaspar BK Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitorsProc Natl Acad Sci USA2008 10543184322

    Not in our library10.1073/pnas.0709144105

  43. 43.

    Liu CM Yang Z Liu CW Wang R Tien P Dale R Sun LQ Myostatin antisense RNA-mediated muscle growth in normal and cancer cachexia miceGene Ther2008 15155160

    Not in our library10.1038/sj.gt.3303016

  44. 44.

    Murphy KT Koopman R Naim T Leger B Trieu J Ibebunjo C Lynch GS Antibody-directed myostatin inhibition in 21-mo-old mice reveals novel roles for myostatin signaling in skeletal muscle structure and functionFASEB J2010 2444334442

    Not in our library10.1096/fj.10-159608

  45. 45.

    Li Z Zhao B Kim YS Hu CY Yang J Administration of a mutated myostatin propeptide to neonatal mice significantly enhances skeletal muscle growthMol Reprod Dev2010 777682

    Not in our library10.1002/mrd.21111

  46. 46.

    Cadena SM Tomkinson KN Monnell TE Spaits MS Kumar R Underwood KW Pearsall RS Lachey JL Administration of a soluble activin type IIB receptor promotes skeletal muscle growth independent of fiber typeJ Appl Physiol2010 109635642

    Not in our library10.1152/japplphysiol.00866.2009

  47. 47.

    Matsakas A Foster K Otto A Macharia R Elashry MI Feist S Graham I Foster H Yaworsky P Walsh F Molecular, cellular and physiological investigation of myostatin propeptide-mediated muscle growth in adult miceNeuromuscul Disord2009 19489499

    Not in our library10.1016/j.nmd.2009.06.367

  48. 48.

    Qiao C Li J Jiang J Zhu X Wang B Xiao X Myostatin propeptide gene delivery by adeno-associated virus serotype 8 vectors enhances muscle growth and ameliorates dystrophic phenotypes in mdx miceHum Gene Ther2008 19241254

    Not in our library10.1089/hum.2007.159

  49. 49.

    Hu S Chen C Sheng J Sun Y Cao X Qiao J Enhanced muscle growth by plasmid-mediated delivery of myostatin propeptideJ Biomed Biotechnol2010 2010862591

    Not in our library10.1155/2010/862591

  50. 50.
    Systemic myostatin inhibition via liver-targeted gene transfer in normal and dystrophic mice. · 2010
    Not checked
  51. 51.

    Serrano AL Munoz-Canoves P Regulation and dysregulation of fibrosis in skeletal muscleExp Cell Res2010 31630503058

    Not in our library10.1016/j.yexcr.2010.05.035

  52. 52.

    Gosselin LE McCormick KM Targeting the immune system to improve ventilatory function in muscular dystrophyMed Sci Sports Exerc2004 364451

    Not in our library10.1249/01.mss.0000106185.22349.2c

  53. 53.

    Allen RE Boxhorn LK Regulation of skeletal muscle satellite cell proliferation and differentiation by transforming growth factor-beta, insulin-like growth factor I, and fibroblast growth factorJ Cell Physiol1989 138311315

    Not in our library10.1002/jcp.1041380213

  54. 54.

    Cohn RD van Erp C Habashi JP Soleimani AA Klein EC Lisi MT Gamradt M ap Rhys CM Holm TM Loeys BL Angiotensin II type 1 receptor blockade attenuates TGF-beta-induced failure of muscle regeneration in multiple myopathic statesNat Med2007 13204210

    Not in our library10.1038/nm1536

  55. 55.

    Spurney CF Sali A Guerron AD Iantorno M Yu Q Gordish-Dressman H Rayavarapu S van der Meulen J Hoffman EP Nagaraju K Losartan decreases cardiac muscle fibrosis and improves cardiac function in dystrophin-deficient mdx miceJ Cardiovasc Pharmacol Ther2011 168795

    Not in our library10.1177/1074248410381757

  56. 56.

    Bedair HS Karthikeyan T Quintero A Li Y Huard J Angiotensin II receptor blockade administered after injury improves muscle regeneration and decreases fibrosis in normal skeletal muscleAm J Sports Med2008 3615481554

    Not in our library10.1177/0363546508315470

  57. 57.

    Taniguti AP Pertille A Matsumura CY Santo Neto H Marques MJ Prevention of muscle fibrosis and myonecrosis in mdx mice by suramin, a TGF-beta1 blockerMuscle Nerve2011 438287

    Not in our library10.1002/mus.21869

  58. 58.

    Nozaki M Li Y Zhu J Ambrosio F Uehara K Fu FH Huard J Improved muscle healing after contusion injury by the inhibitory effect of suramin on myostatin, a negative regulator of muscle growthAm J Sports Med2008 3623542362

    Not in our library10.1177/0363546508322886

  59. 59.

    Chan YS Li Y Foster W Horaguchi T Somogyi G Fu FH Huard J Antifibrotic effects of suramin in injured skeletal muscle after lacerationJ Appl Physiol2003 95771780

    Not in our library10.1152/japplphysiol.00915.2002

  60. 60.

    Chan YS Li Y Foster W Fu FH Huard J The use of suramin, an antifibrotic agent, to improve muscle recovery after strain injuryAm J Sports Med2005 334351

    Not in our library10.1177/0363546504265190

  61. 61.

    Fukushima K Badlani N Usas A Riano F Fu F Huard J The use of an antifibrosis agent to improve muscle recovery after lacerationAm J Sports Med2001 29394402

    Not in our library10.1177/03635465010290040201

  62. 62.

    Gosselin LE Williams JE Deering M Brazeau D Koury S Martinez DA Localization and early time course of TGF-beta 1 mRNA expression in dystrophic muscleMuscle Nerve2004 30645653

    Not in our library10.1002/mus.20150

  63. 63.

    Foster W Li Y Usas A Somogyi G Huard J Gamma interferon as an antifibrosis agent in skeletal muscleJ Orthop Res2003 21798804

    Not in our library10.1016/s0736-0266(03)00059-7

  64. 64.

    Van Erp C Irwin NG Hoey AJ Long-term administration of pirfenidone improves cardiac function in mdx miceMuscle Nerve2006 34327334

    Not in our library10.1002/mus.20590

  65. 65.

    Gosselin LE Williams JE Personius K Farkas GA A comparison of factors associated with collagen metabolism in different skeletal muscles from dystrophic (mdx) mice: impact of pirfenidoneMuscle Nerve2007 35208216

    Not in our library10.1002/mus.20681

  66. 66.

    Turgeman T Hagai Y Huebner K Jassal DS Anderson JE Genin O Nagler A Halevy O Pines M Prevention of muscle fibrosis and improvement in muscle performance in the mdx mouse by halofuginoneNeuromuscul Disord2008 18857868

    Not in our library10.1016/j.nmd.2008.06.386

  67. 67.

    Huebner KD Jassal DS Halevy O Pines M Anderson JE Functional resolution of fibrosis in mdx mouse dystrophic heart and skeletal muscle by halofuginoneAm J Physiol Heart Circ Physiol2008 294H15501561

    Not in our library10.1152/ajpheart.01253.2007

  68. 68.

    Nevo Y Halevy O Genin O Moshe I Turgeman T Harel M Biton E Reif S Pines M Fibrosis inhibition and muscle histopathology improvement in laminin-alpha2-deficient miceMuscle Nerve2010 42218229

    Not in our library10.1002/mus.21706

  69. 69.

    Andreetta F Bernasconi P Baggi F Ferro P Oliva L Arnoldi E Cornelio F Mantegazza R Confalonieri P Immunomodulation of TGF-beta 1 in mdx mouse inhibits connective tissue proliferation in diaphragm but increases inflammatory response: implications for antifibrotic therapyJ Neuroimmunol2006 1757786

    Not in our library10.1016/j.jneuroim.2006.03.005

  70. 70.
    Relative roles of TGF‐β1 and Wnt in the systemic regulation and aging of satellite cell responses · 2009
    No notice
  71. 71.

    McCroskery S Thomas M Platt L Hennebry A Nishimura T McLeay L Sharma M Kambadur R Improved muscle healing through enhanced regeneration and reduced fibrosis in myostatin-null miceJ Cell Sci2005 11835313541

    Not in our library10.1242/jcs.02482

  72. 72.

    Zhu J Li Y Shen W Qiao C Ambrosio F Lavasani M Nozaki M Branca MF Huard J Relationships between transforming growth factor-beta1, myostatin, and decorin: implications for skeletal muscle fibrosisJ Biol Chem2007 2822585225863

    Not in our library10.1074/jbc.m704146200

  73. 73.

    Li ZB Kollias HD Wagner KR Myostatin directly regulates skeletal muscle fibrosisJ Biol Chem2008 2831937119378

    Not in our library10.1074/jbc.m802585200

  74. 74.

    McCroskery S Thomas M Maxwell L Sharma M Kambadur R Myostatin negatively regulates satellite cell activation and self-renewalJ Cell Biol2003 16211351147

    Not in our library10.1083/jcb.200207056

  75. 75.

    Carnac G Vernus B Bonnieu A Myostatin in the pathophysiology of skeletal muscleCurr Genomics2007 8415422

    Not in our library10.2174/138920207783591672

  76. 76.

    Langley B Thomas M Bishop A Sharma M Gilmour S Kambadur R Myostatin inhibits myoblast differentiation by down-regulating MyoD expressionJ Biol Chem2002 2774983149840

    Not in our library10.1074/jbc.m204291200

  77. 77.

    Joulia D Bernardi H Garandel V Rabenoelina F Vernus B Cabello G Mechanisms involved in the inhibition of myoblast proliferation and differentiation by myostatinExp Cell Res2003 286263275

    Not in our library10.1016/s0014-4827(03)00074-0

  78. 78.

    Bogdanovich S Krag TO Barton ER Morris LD Whittemore LA Ahima RS Khurana TS Functional improvement of dystrophic muscle by myostatin blockadeNature2002 420418421

    Not in our library10.1038/nature01154

  79. 79.

    Murphy KT Ryall JG Snell SM Nair L Koopman R Krasney PA Ibebunjo C Holden KS Loria PM Salatto CT Lynch GS Antibody-directed myostatin inhibition improves diaphragm pathology in young but not adult dystrophic mdx miceAm J Pathol2010 17624252434

    Not in our library10.2353/ajpath.2010.090932

  80. 80.

    Bogdanovich S McNally EM Khurana TS Myostatin blockade improves function but not histopathology in a murine model of limb-girdle muscular dystrophy 2CMuscle Nerve2008 37308316

    Not in our library10.1002/mus.20920

  81. 81.

    Parsons SA Millay DP Sargent MA McNally EM Molkentin JD Age-dependent effect of myostatin blockade on disease severity in a murine model of limb-girdle muscular dystrophyAm J Pathol2006 16819751985

    Not in our library10.2353/ajpath.2006.051316

  82. 82.

    Holzbaur EL Howland DS Weber N Wallace K She Y Kwak S Tchistiakova LA Murphy E Hinson J Karim R Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosisNeurobiol Dis2006 23697707

    Not in our library10.1016/j.nbd.2006.05.009

  83. 83.

    LeBrasseur NK Schelhorn TM Bernardo BL Cosgrove PG Loria PM Brown TA Myostatin inhibition enhances the effects of exercise on performance and metabolic outcomes in aged miceJ Gerontol A Biol Sci Med Sci2009 64940948

    Not in our library10.1093/gerona/glp068

  84. 84.

    Morine KJ Bish LT Selsby JT Gazzara JA Pendrak K Sleeper MM Barton ER Lee SJ Sweeney HL Activin IIB receptor blockade attenuates dystrophic pathology in a mouse model of Duchenne muscular dystrophyMuscle Nerve2010 42722730

    Not in our library10.1002/mus.21743

  85. 85.

    Ohsawa Y Hagiwara H Nakatani M Yasue A Moriyama K Murakami T Tsuchida K Noji S Sunada Y Muscular atrophy of caveolin-3-deficient mice is rescued by myostatin inhibitionJ Clin Invest2006 11629242934

    Not in our library10.1172/jci28520

  86. 86.

    Sumner CJ Wee CD Warsing LC Choe DW Ng AS Lutz C Wagner KR Inhibition of myostatin does not ameliorate disease features of severe spinal muscular atrophy miceHum Mol Genet2009 1831453152

    Not in our library10.1093/hmg/ddp253

  87. 87.

    Morrison BM Lachey JL Warsing LC Ting BL Pullen AE Underwood KW Kumar R Sako D Grinberg A Wong V A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosisExp Neurol2009 217258268

    Not in our library10.1016/j.expneurol.2009.02.017

  88. 88.

    Benny Klimek ME Aydogdu T Link MJ Pons M Koniaris LG Zimmers TA Acute inhibition of myostatin-family proteins preserves skeletal muscle in mouse models of cancer cachexiaBiochem Biophys Res Commun2010 39115481554

    Not in our library10.1016/j.bbrc.2009.12.123

  89. 89.

    Zhou X Wang JL Lu J Song Y Kwak KS Jiao Q Rosenfeld R Chen Q Boone T Simonet WS Reversal of cancer cachexia and muscle wasting by ActRIIB antagonism leads to prolonged survivalCell2010 142531543

    Not in our library10.1016/j.cell.2010.07.011

  90. 90.

    Bogdanovich S Perkins KJ Krag TO Whittemore LA Khurana TS Myostatin propeptide-mediated amelioration of dystrophic pathophysiologyFASEB J2005 19543549

    Not in our library10.1096/fj.04-2796com

  91. 91.

    Bartoli M Poupiot J Vulin A Fougerousse F Arandel L Daniele N Roudaut C Noulet F Garcia L Danos O Richard I AAV-mediated delivery of a mutated myostatin propeptide ameliorates calpain 3 but not alpha-sarcoglycan deficiencyGene Ther2007 14733740

    Not in our library10.1038/sj.gt.3302928

  92. 92.

    Hamrick MW Arounleut P Kellum E Cain M Immel D Liang LF Recombinant myostatin (GDF-8) propeptide enhances the repair and regeneration of both muscle and bone in a model of deep penetrant musculoskeletal injuryJ Trauma2010 69579583

    Not in our library10.1097/ta.0b013e3181c451f4

  93. 93.

    Rose FF Jr Mattis VB Rindt H Lorson CL Delivery of recombinant follistatin lessens disease severity in a mouse model of spinal muscular atrophyHum Mol Genet2009 189971005

    Not in our library10.1093/hmg/ddn426

  94. 94.

    Miller TM Kim SH Yamanaka K Hester M Umapathi P Arnson H Rizo L Mendell JR Gage FH Cleveland DW Kaspar BK Gene transfer demonstrates that muscle is not a primary target for non-cell-autonomous toxicity in familial amyotrophic lateral sclerosisProc Natl Acad Sci USA2006 1031954619551

    Not in our library10.1073/pnas.0609411103

  95. 95.

    Minetti GC Colussi C Adami R Serra C Mozzetta C Parente V Fortuni S Straino S Sampaolesi M Di Padova M Functional and morphological recovery of dystrophic muscles in mice treated with deacetylase inhibitorsNat Med2006 1211471150

    Not in our library10.1038/nm1479

  96. 96.

    Bonetto A Penna F Minero VG Reffo P Bonelli G Baccino FM Costelli P Deacetylase inhibitors modulate the myostatin/follistatin axis without improving cachexia in tumor-bearing miceCurr Cancer Drug Targets2009 9608616

    Not in our library10.2174/156800909789057015

  97. 97.

    Iezzi S Di Padova M Serra C Caretti G Simone C Maklan E Minetti G Zhao P Hoffman EP Puri PL Sartorelli V Deacetylase inhibitors increase muscle cell size by promoting myoblast recruitment and fusion through induction of follistatinDev Cell2004 6673684

    Not in our library10.1016/s1534-5807(04)00107-8

  98. 98.

    Siriett V Platt L Salerno MS Ling N Kambadur R Sharma M Prolonged absence of myostatin reduces sarcopeniaJ Cell Physiol2006 209866873

    Not in our library10.1002/jcp.20778

  99. 99.

    Murphy KT Cobani V Ryall JG Ibebunjo C Lynch GS Acute antibody-directed myostatin inhibition attenuates disuse muscle atrophy and weakness in miceJ Appl Physiol2011

    Not in our library10.1152/japplphysiol.01183.2010

  100. 100.

    Pistilli EE Bogdanovich S Goncalves MD Ahima RS Lachey J Seehra J Khurana T Targeting the activin type IIB Receptor to improve muscle mass and function in the mdx mouse model of Duchenne muscular dystrophyAm J Pathol2011 17812871297

    Not in our library10.1016/j.ajpath.2010.11.071

  101. 101.

    Millino C Fanin M Vettori A Laveder P Mostacciuolo ML Angelini C Lanfranchi G Different atrophy-hypertrophy transcription pathways in muscles affected by severe and mild spinal muscular atrophyBMC Med2009 714

    Not in our library10.1186/1741-7015-7-14

  102. 102.

    Katsuno M Adachi H Minamiyama M Waza M Doi H Kondo N Mizoguchi H Nitta A Yamada K Banno H Disrupted transforming growth factor-beta signaling in spinal and bulbar muscular atrophyJ Neurosci2010 3057025712

    Not in our library10.1523/jneurosci.0388-10.2010

  103. 103.

    Dietz HC Cutting GR Pyeritz RE Maslen CL Sakai LY Corson GM Puffenberger EG Hamosh A Nanthakumar EJ Curristin SM Marfan syndrome caused by a recurrent de novo missense mutation in the fibrillin geneNature1991 352337339

    Not in our library10.1038/352337a0

  104. 104.

    Morgan JE Zammit PS Direct effects of the pathogenic mutation on satellite cell function in muscular dystrophyExp Cell Res2010 31631003108

    Not in our library10.1016/j.yexcr.2010.05.014

  105. 105.

    Cohn RD Campbell KP Molecular basis of muscular dystrophiesMuscle Nerve2000 2314561471

    Not in our library10.1002/1097-4598(200010)23:10<1456::aid-mus2>3.0.co;2-t

  106. 106.

    Bernasconi P Di Blasi C Mora M Morandi L Galbiati S Confalonieri P Cornelio F Mantegazza R Transforming growth factor-beta1 and fibrosis in congenital muscular dystrophiesNeuromuscul Disord1999 92833

    Not in our library10.1016/s0960-8966(98)00093-5

  107. 107.

    Ishitobi M Haginoya K Zhao Y Ohnuma A Minato J Yanagisawa T Tanabu M Kikuchi M Iinuma K Elevated plasma levels of transforming growth factor beta1 in patients with muscular dystrophyNeuroreport2000 1140334035

    Not in our library10.1097/00001756-200012180-00026

  108. 108.

    Passerini L Bernasconi P Baggi F Confalonieri P Cozzi F Cornelio F Mantegazza R Fibrogenic cytokines and extent of fibrosis in muscle of dogs with X-linked golden retriever muscular dystrophyNeuromuscul Disord2002 12828835

    Not in our library10.1016/s0960-8966(02)00071-8

  109. 109.

    Zanotti S Negri T Cappelletti C Bernasconi P Canioni E Di Blasi C Pegoraro E Angelini C Ciscato P Prelle A Decorin and biglycan expression is differentially altered in several muscular dystrophiesBrain2005 12825462555

    Not in our library10.1093/brain/awh635

  110. 110.

    Zanotti S Saredi S Ruggieri A Fabbri M Blasevich F Romaggi S Morandi L Mora M Altered extracellular matrix transcript expression and protein modulation in primary Duchenne muscular dystrophy myotubesMatrix Biol2007 26615624

    Not in our library10.1016/j.matbio.2007.06.004

  111. 111.

    Muchir A Pavlidis P Bonne G Hayashi YK Worman HJ Activation of MAPK in hearts of EMD null mice: similarities between mouse models of X-linked and autosomal dominant Emery Dreifuss muscular dystrophyHum Mol Genet2007 1618841895

    Not in our library10.1093/hmg/ddm137

  112. 112.

    Muchir A Pavlidis P Decostre V Herron AJ Arimura T Bonne G Worman HJ Activation of MAPK pathways links LMNA mutations to cardiomyopathy in Emery-Dreifuss muscular dystrophyJ Clin Invest2007 11712821293

    Not in our library10.1172/jci29042

  113. 113.

    Griffin MA Feng H Tewari M Acosta P Kawana M Sweeney HL Discher DE gamma-Sarcoglycan deficiency increases cell contractility, apoptosis and MAPK pathway activation but does not affect adhesionJ Cell Sci2005 11814051416

    Not in our library10.1242/jcs.01717

  114. 114.

    Woodman SE Park DS Cohen AW Cheung MW Chandra M Shirani J Tang B Jelicks LA Kitsis RN Christ GJ Caveolin-3 knock-out mice develop a progressive cardiomyopathy and show hyperactivation of the p42/44 MAPK cascadeJ Biol Chem2002 2773898838997

    Not in our library10.1074/jbc.m205511200

  115. 115.

    Markert CD Meaney MP Voelker KA Grange RW Dalley HW Cann JK Ahmed M Bishwokarma B Walker SJ Yu SX Functional muscle analysis of the Tcap knockout mouseHum Mol Genet2010 1922682283

    Not in our library10.1093/hmg/ddq105

  116. 116.

    Chen YW Nagaraju K Bakay M McIntyre O Rawat R Shi R Hoffman EP Early onset of inflammation and later involvement of TGFbeta in Duchenne muscular dystrophyNeurology2005 65826834

    Not in our library10.1212/01.wnl.0000173836.09176.c4

  117. 117.

    Porter JD Khanna S Kaminski HJ Rao JS Merriam AP Richmonds CR Leahy P Li J Guo W Andrade FH A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx miceHum Mol Genet2002 11263272

    Not in our library10.1093/hmg/11.3.263

  118. 118.

    Vetrone SA Montecino-Rodriguez E Kudryashova E Kramerova I Hoffman EP Liu SD Miceli MC Spencer MJ Osteopontin promotes fibrosis in dystrophic mouse muscle by modulating immune cell subsets and intramuscular TGF-betaJ Clin Invest2009 11915831594

    Not in our library10.1172/jci37662

  119. 119.

    Zanotti S Gibertini S Mora M Altered production of extra-cellular matrix components by muscle-derived Duchenne muscular dystrophy fibroblasts before and after TGF-beta1 treatmentCell Tissue Res2010 339397410

    Not in our library10.1007/s00441-009-0889-4

  120. 120.

    Sun G Haginoya K Wu Y Chiba Y Nakanishi T Onuma A Sato Y Takigawa M Iinuma K Tsuchiya S Connective tissue growth factor is overexpressed in muscles of human muscular dystrophyJ Neurol Sci2008 2674856

    Not in our library10.1016/j.jns.2007.09.043

  121. 121.

    Kumar A Khandelwal N Malya R Reid MB Boriek AM Loss of dystrophin causes aberrant mechanotransduction in skeletal muscle fibersFASEB J2004 18102113

    Not in our library10.1096/fj.03-0453com

  122. 122.

    Kolodziejczyk SM Walsh GS Balazsi K Seale P Sandoz J Hierlihy AM Rudnicki MA Chamberlain JS Miller FD Megeney LA Activation of JNK1 contributes to dystrophic muscle pathogenesisCurr Biol2001 1112781282

    Not in our library10.1016/s0960-9822(01)00397-9

  123. 123.

    Nakamura A Harrod GV Davies KE Activation of calcineurin and stress activated protein kinase/p38-mitogen activated protein kinase in hearts of utrophin-dystrophin knockout miceNeuromuscul Disord2001 11251259

    Not in our library10.1016/s0960-8966(00)00201-7

  124. 124.

    Vidal B Serrano AL Tjwa M Suelves M Ardite E De Mori R Baeza-Raja B Martinez de Lagran M Lafuste P Ruiz-Bonilla V Fibrinogen drives dystrophic muscle fibrosis via a TGFbeta/alternative macrophage activation pathwayGenes Dev2008 2217471752

    Not in our library10.1101/gad.465908

  125. 125.

    Goldstein JA Kelly SM Lopresti PP Heydemann A Earley JU Ferguson EL Wolf MJ McNally EM SMAD signaling drives heart and muscle dysfunction in a Drosophila model of muscular dystrophyHum Mol Genet2010

    Not in our library10.1093/hmg/ddq528

  126. 126.

    Hayot M Rodriguez J Vernus B Carnac G Jean E Allen D Goret L Obert P Candau R Bonnieu A Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuliMol Cell Endocrinol2011 3323847

    Not in our library10.1016/j.mce.2010.09.008

  127. 127.

    Lalani R Bhasin S Byhower F Tarnuzzer R Grant M Shen R Asa S Ezzat S Gonzalez-Cadavid NF Myostatin and insulin-like growth factor-I and -II expression in the muscle of rats exposed to the microgravity environment of the NeuroLab space shuttle flightJ Endocrinol2000 167417428

    Not in our library10.1677/joe.0.1670417

  128. 128.

    Allen DL Cleary AS Lindsay SF Loh AS Reed JM Myostatin expression is increased by food deprivation in a muscle-specific manner and contributes to muscle atrophy during prolonged food deprivation in miceJ Appl Physiol2010 109692701

    Not in our library10.1152/japplphysiol.00504.2010

  129. 129.

    Allen DL McCall GE Loh AS Madden MC Mehan RS Acute daily psychological stress causes increased atrophic gene expression and myostatin-dependent muscle atrophyAm J Physiol Regul Integr Comp Physiol2010 299R889898

    Not in our library10.1152/ajpregu.00296.2010

  130. 130.

    Wehling M Cai B Tidball JG Modulation of myostatin expression during modified muscle useFASEB J2000 14103110

    Not in our library10.1096/fasebj.14.1.103

  131. 131.

    Heinemeier KM Olesen JL Haddad F Schjerling P Baldwin KM Kjaer M Effect of unloading followed by reloading on expression of collagen and related growth factors in rat tendon and muscleJ Appl Physiol2009 106178186

    Not in our library10.1152/japplphysiol.91092.2008

  132. 132.

    Jones SW Hill RJ Krasney PA O'Conner B Peirce N Greenhaff PL Disuse atrophy and exercise rehabilitation in humans profoundly affects the expression of genes associated with the regulation of skeletal muscle massFASEB J2004 1810251027

    Not in our library10.1096/fj.03-1228fje

  133. 133.

    Kim J Won KJ Lee HM Hwang BY Bae YM Choi WS Song H Lim KW Lee CK Kim B p38 MAPK participates in muscle-specific RING finger 1-Mediated atrophy in cast-immobilized rat gastrocnemius muscleKorean J Physiol Pharmacol2009 13491496

    Not in our library10.4196/kjpp.2009.13.6.491

  134. 134.

    Reardon KA Davis J Kapsa RM Choong P Byrne E Myostatin, insulin-like growth factor-1, and leukemia inhibitory factor mRNAs are upregulated in chronic human disuse muscle atrophyMuscle Nerve2001 24893899

    Not in our library10.1002/mus.1086

  135. 135.

    Hirose T Nakazato K Song H Ishii N TGF-beta1 and TNF-alpha are involved in the transcription of type I collagen alpha2 gene in soleus muscle atrophied by mechanical unloadingJ Appl Physiol2008 104170177

    Not in our library10.1152/japplphysiol.00463.2006

  136. 136.

    Machida S Booth FW Changes in signalling molecule levels in 10-day hindlimb immobilized rat musclesActa Physiol Scand2005 183171179

    Not in our library10.1111/j.1365-201x.2004.01395.x

  137. 137.

    Carlson CJ Booth FW Gordon SE Skeletal muscle myostatin mRNA expression is fiber-type specific and increases during hindlimb unloadingAm J Physiol1999 277R601606

    Not in our library10.1152/ajpregu.1999.277.2.r601

  138. 138.

    Costelli P Muscaritoli M Bonetto A Penna F Reffo P Bossola M Bonelli G Doglietto GB Baccino FM Rossi Fanelli F Muscle myostatin signalling is enhanced in experimental cancer cachexiaEur J Clin Invest2008 38531538

    Not in our library10.1111/j.1365-2362.2008.01970.x

  139. 139.

    Tanaka M Miyazaki H Takeda Y Takeo S Detection of serum cytokine levels in experimental cancer cachexia of colon 26 adenocarcinoma-bearing miceCancer Lett1993 726570

    Not in our library10.1016/0304-3835(93)90012-x

  140. 140.

    Houi K Kobayashi T Kato S Mochio S Inoue K Increased plasma TGF-beta1 in patients with amyotrophic lateral sclerosisActa Neurol Scand2002 106299301

    Not in our library10.1034/j.1600-0404.2002.01301.x

  141. 141.

    Gonzalez-Cadavid NF Taylor WE Yarasheski K Sinha-Hikim I Ma K Ezzat S Shen R Lalani R Asa S Mamita M Organization of the human myostatin gene and expression in healthy men and HIV-infected men with muscle wastingProc Natl Acad Sci USA1998 951493814943

    Not in our library10.1073/pnas.95.25.14938

  142. 142.

    Ma K Mallidis C Bhasin S Mahabadi V Artaza J Gonzalez-Cadavid N Arias J Salehian B Glucocorticoid-induced skeletal muscle atrophy is associated with upregulation of myostatin gene expressionAm J Physiol Endocrinol Metab2003 285E363371

    Not in our library10.1152/ajpendo.00487.2002

  143. 143.

    Roubenoff R Sarcopenia and its implications for the elderlyEur J Clin Nutr2000 54Suppl 3S4047

    Not in our library10.1038/sj.ejcn.1601024

  144. 144.

    Machida S Narusawa M The roles of satellite cells and hematopoietic stem cells in impaired regeneration of skeletal muscle in old ratsAnn N Y Acad Sci2006 1067349353

    Not in our library10.1196/annals.1354.049

  145. 145.

    Carlson ME Hsu M Conboy IM Imbalance between pSmad3 and Notch induces CDK inhibitors in old muscle stem cellsNature2008 454528532

    Not in our library10.1038/nature07034

  146. 146.

    Carlson ME Suetta C Conboy MJ Aagaard P Mackey A Kjaer M Conboy I Molecular aging and rejuvenation of human muscle stem cellsEMBO Mol Med2009 1381391

    Not in our library10.1002/emmm.200900045

  147. 147.

    Leger B Derave W De Bock K Hespel P Russell AP Human sarcopenia reveals an increase in SOCS-3 and myostatin and a reduced efficiency of Akt phosphorylationRejuvenation Res2008 11163175B

    Not in our library10.1089/rej.2007.0588

  148. 148.

    Puthucheary Z Harridge S Hart N Skeletal muscle dysfunction in critical care: wasting, weakness, and rehabilitation strategiesCrit Care Med2010 38S676682

    Not in our library10.1097/ccm.0b013e3181f2458d

  149. 149.

    Di Giovanni S Molon A Broccolini A Melcon G Mirabella M Hoffman EP Servidei S Constitutive activation of MAPK cascade in acute quadriplegic myopathyAnn Neurol2004 55195206

    Not in our library10.1002/ana.10811

  150. 150.

    Lavoie P Robitaille G Agharazii M Ledbetter S Lebel M Lariviere R Neutralization of transforming growth factor-beta attenuates hypertension and prevents renal injury in uremic ratsJ Hypertens2005 2318951903

    Not in our library10.1097/01.hjh.0000182521.44440.c5

  151. 151.

    Lim DS Lutucuta S Bachireddy P Youker K Evans A Entman M Roberts R Marian AJ Angiotensin II blockade reverses myocardial fibrosis in a transgenic mouse model of human hypertrophic cardiomyopathyCirculation2001 103789791

    Not in our library10.1161/01.cir.103.6.789

  152. 152.

    Rodriguez-Vita J Sanchez-Lopez E Esteban V Ruperez M Egido J Ruiz-Ortega M Angiotensin II activates the Smad pathway in vascular smooth muscle cells by a transforming growth factor-beta-independent mechanismCirculation2005 11125092517

    Not in our library10.1161/01.cir.0000165133.84978.e2

  153. 153.

    Hirata A Masuda S Tamura T Kai K Ojima K Fukase A Motoyoshi K Kamakura K Miyagoe-Suzuki Y Takeda S Expression profiling of cytokines and related genes in regenerating skeletal muscle after cardiotoxin injection: a role for osteopontinAm J Pathol2003 163203215

    Not in our library10.1016/s0002-9440(10)63644-9

  154. 154.

    Pereira RO Carvalho SN Stumbo AC Rodrigues CA Porto LC Moura AS Carvalho L Osteopontin expression in coculture of differentiating rat fetal skeletal fibroblasts and myoblastsIn Vitro Cell Dev Biol Anim2006 4247

    Not in our library10.1007/s11626-006-0003-0

  155. 155.

    Uaesoontrachoon K Yoo HJ Tudor EM Pike RN Mackie EJ Pagel CN Osteopontin and skeletal muscle myoblasts: association with muscle regeneration and regulation of myoblast function in vitroInt J Biochem Cell Biol2008 4023032314

    Not in our library10.1016/j.biocel.2008.03.020

  156. 156.

    Wagner KR McPherron AC Winik N Lee SJ Loss of myostatin attenuates severity of muscular dystrophy in mdx miceAnn Neurol2002 52832836

    Not in our library10.1002/ana.10385

  157. 157.

    Gilson H Schakman O Combaret L Lause P Grobet L Attaix D Ketelslegers JM Thissen JP Myostatin gene deletion prevents glucocorticoid-induced muscle atrophyEndocrinology2007 148452460

    Not in our library10.1210/en.2006-0539

  158. 158.

    Li ZF Shelton GD Engvall E Elimination of myostatin does not combat muscular dystrophy in dy mice but increases postnatal lethalityAm J Pathol2005 166491497

    Not in our library10.1016/s0002-9440(10)62271-7

  159. 159.

    McMahon CD Popovic L Oldham JM Jeanplong F Smith HK Kambadur R Sharma M Maxwell L Bass JJ Myostatin-deficient mice lose more skeletal muscle mass than wild-type controls during hindlimb suspensionAm J Physiol Endocrinol Metab2003 285E8287

    Not in our library10.1152/ajpendo.00275.2002

  160. 160.

    Amthor H Macharia R Navarrete R Schuelke M Brown SC Otto A Voit T Muntoni F Vrbova G Partridge T Lack of myostatin results in excessive muscle growth but impaired force generationProc Natl Acad Sci USA2007 10418351840

    Not in our library10.1073/pnas.0604893104

  161. 161.

    Gentry BA Ferreira JA Phillips CL Brown M Hindlimb skeletal muscle function in myostatin-deficient miceMuscle Nerve2011 434957

    Not in our library10.1002/mus.21796

  162. 162.

    Mendias CL Bakhurin KI Faulkner JA Tendons of myostatin-deficient mice are small, brittle, and hypocellularProc Natl Acad Sci USA2008 105388393

    Not in our library10.1073/pnas.0707069105

  163. 163.
    Muscle Wasting and Impaired Myogenesis in Tumor Bearing Mice Are Prevented by ERK Inhibition · 2010
    No notice
  164. 164.

    Wu W Shan J Bonne G Worman HJ Muchir A Pharmacological inhibition of c-Jun N-terminal kinase signaling prevents cardiomyopathy caused by mutation in LMNA geneBiochim Biophys Acta2010 1802632638

    Not in our library10.1016/j.bbadis.2010.04.001

  165. 165.

    Muchir A Shan J Bonne G Lehnart SE Worman HJ Inhibition of extracellular signal-regulated kinase signaling to prevent cardiomyopathy caused by mutation in the gene encoding A-type laminsHum Mol Genet2009 18241247

    Not in our library10.1093/hmg/ddn343

  166. 166.

    Wu W Muchir A Shan J Bonne G Worman HJ Mitogen-activated protein kinase inhibitors improve heart function and prevent fibrosis in cardiomyopathy caused by mutation in lamin A/C geneCirculation2011 1235361

    Not in our library10.1161/circulationaha.110.970673

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