A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis

Morrison, Brett M.; Lachey, Jennifer; Warsing, Leigh C.; Ting, Beverlie L.; Pullen, Abigail E.; Underwood, Kathryn; Kumar, Ravindra; Sako, Dianne; Grinberg, Asya V.; Wong, Vicki L.; Colantuoni, Elizabeth; Seehra, Jasbir; Wagner, Kathryn R.

doi:10.1016/j.expneurol.2009.02.017

Cited by 74 publications

(84 citation statements)

References 33 publications

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“…The chimeric fusion protein, ActRIIB.mFc, has been shown to inhibit activation of the myostatin pathway in vitro and in vivo (Lee et al, 2005;Morrison et al, 2009;Sako et al, 2010). We found that ActRIIB.mFc (a gift from Acceleron Pharma) can block collagen synthesis induced by exogenous myostatin stimulation of mdx muscle fibroblasts as measured by 3 H-proline incorporation with an IC 50 of approximately 1 nM (Fig.…”

Section: Myostatin Regulates Proliferation and Ecm Production Of Dystmentioning

confidence: 74%

“…In some but not all studies, postnatal myostatin inhibition has resulted in increased muscle mass and muscle strength with less fibrosis in treated animals compared to controls. The soluble receptor, ActRIIB.mFc, is a potent inhibitor of myostatin as well as activins and growth differentiation factor 11 (GDF11) (Lee et al, 2005, Morrison et al, 2009Sako et al, 2010). In the current study, ActRIIB.mFc increased muscle growth and regeneration in senescent mdx mice treated for 6 weeks.…”

Section: Discussionmentioning

confidence: 99%

“…Two-year-old mdx mice were systemically administered PBS as control or 10 mg/kg ActRIIB.mFc for 6 weeks, a dose previously determined to induce muscle hypertrophy in wild-type mice (Akpan et al, 2009;Cadena et al, 2010;Lachey et al, 2007;Morrison et al, 2009). Apoptotic cells in the interstitial space between muscle fibers were identified by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and by immunohistochemistry assay of cleaved caspase-3 (Fig.…”

Section: Myostatin Regulates Proliferation and Ecm Production Of Dystmentioning

confidence: 99%

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Inhibiting myostatin reverses muscle fibrosis through apoptosis

Zhang

Wagner

2012

Journal of Cell Science

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SummarySkeletal muscle fibrosis is a defining feature of the muscular dystrophies in which contractile myofibers are replaced by fibroblasts, adipocytes and extracellular matrix. This maladaptive response of muscle to repetitive injury is progressive, self-perpetuating and thus far, has been considered irreversible. We have previously shown that myostatin, a known endogenous modulator of muscle growth, stimulates normal muscle fibroblasts to proliferate. Here, we demonstrate that myostatin also regulates the proliferation of dystrophic muscle fibroblasts, and increases resistance of fibroblasts to apoptosis through Smad and MAPK signaling. Inhibition of myostatin signaling pathways with a soluble activin IIB receptor (ActRIIB.Fc) reduces resistance of muscle fibroblasts to apoptosis in vitro. Systemic administration of ActRIIB.Fc in senescent mdx mice, a model of muscular dystrophy, significantly increases the number of muscle fibroblasts undergoing apoptosis. This leads to the reversal of pre-existing muscle fibrosis as determined by histological, biochemical and radiographical criteria. These results demonstrate that skeletal muscle fibrosis can be pharmacologically reversed through induction of fibroblast apoptosis.

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Section: Myostatin Regulates Proliferation and Ecm Production Of Dystmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

Section: Myostatin Regulates Proliferation and Ecm Production Of Dystmentioning

confidence: 99%

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Inhibiting myostatin reverses muscle fibrosis through apoptosis

Zhang

Wagner

2012

Journal of Cell Science

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“…In effect, myostatin is a skeletal muscle-specific secreted peptide that essentially modulates myoblast proliferation and thus muscle mass/strength . Preclinical trials using myostatin loss or inhibition have been effective in ameliorating symptoms of weakness in several animal Klimek et al 2010;Bogdanovich et al 2002;Lee and McPherron 2001;Liu et al 2008;Morrison et al 2009;Murphy et al 2010;Qiao et al 2009;Siriett et al 2006;Tsuchida 2008;Wagner et al 2008;Zhu et al 2007). In humans, myostatin inhibitors, such as MYO-029, have an adequate safety margin and are able to improve the muscle strength/function or muscle contractile properties in some patients with muscular dystrophy (Krivickas et al 2009;Wagner et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…Myostatin loss or inhibition has proven effective in ameliorating symptoms of weakness in several animal models of muscle injury, atrophy and disease (Benny Klimek et al 2010;Bogdanovich et al 2002;Lee and McPherron 2001;Liu et al 2008;Morrison et al 2009;Murphy et al 2010;Qiao et al 2009;Siriett et al 2006;Tsuchida 2008;Wagner et al 2008;Zhu et al 2007). Myostatin inhibition, as well as variations in the MSTN gene, can also have functional consequences in humans.…”

Section: Introductionmentioning

confidence: 99%

Association of the K153R polymorphism in the myostatin gene and extreme longevity

Garatachea

Pinós

Cámara

et al. 2013

AGE

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The myostatin (MSTN) gene is a candidate to influence extreme longevity owing to its role in modulating muscle mass and sarcopenia and especially in inhibiting the main nutrient-sensing pathway involved in longevity, i.e. mammalian target of rapamycin. We compared allele/genotype distributions of the exonic MSTN variants K153R (rs1805086), E164K (rs35781413), I225T and P198A, in Spanish centenarians (cases, n=156; 132 women, age range 100-111 years) and younger adults (controls, n=384; 167 women, age <50 years). No subject of either group carried a mutant allele of the E164K, I225T or AGE (2013) 35:2445-2454 DOI 10.1007 Antoni L. Andreu and Alejandro Lucia share senior authorship. P198A variation. The frequency of the variant R allele was significantly higher in centenarians (7.1 %) than in controls (2.7 %) (P=0.001). The odds ratio of being a centenarian if the subject had the R allele was 3.48 (95 % confidence interval 1.67-7.28, P=0.001), compared to the control group, after adjusting for sex. The results were replicated in an Italian cohort (centenarians, n=79 (40 women), age range 100-104 years; younger controls, n=316 (155 women), age <50 years), where a higher frequency of the R allele in centenarians (7.6 %) compared to controls (3.0 %) (P=0.004) was independently confirmed. Although more research is needed, the variant allele of the MSTN K153R polymorphism could be among the genetic contributors associated with exceptional longevity.

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Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

Maragakis,

de Carvalho,

Weiss

2023

Ann Clin Transl Neurol

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Numerous potential amyotrophic lateral sclerosis (ALS)‐relevant pathways have been hypothesized and studied preclinically, with subsequent translation to clinical trial. However, few successes have been observed with only modest effects. Along with an improved but incomplete understanding of ALS as a neurodegenerative disease is the evolution of more sophisticated and diverse in vitro and in vivo preclinical modeling platforms, as well as clinical trial designs. We highlight proposed pathological pathways that have been major therapeutic targets for investigational compounds. It is likely that the failures of so many of these therapeutic compounds may not have occurred because of lack of efficacy but rather because of a lack of preclinical modeling that would help define an appropriate disease pathway, as well as a failure to establish target engagement. These challenges are compounded by shortcomings in clinical trial design, including lack of biomarkers that could predict clinical success and studies that are underpowered. Although research investments have provided abundant insights into new ALS‐relevant pathways, most have not yet been developed more fully to result in clinical study. In this review, we detail some of the important, well‐established pathways, the therapeutics targeting them, and the subsequent clinical design. With an understanding of some of the shortcomings in translational efforts over the last three decades of ALS investigation, we propose that scientists and clinicians may choose to revisit some of these therapeutic pathways reviewed here with an eye toward improving preclinical modeling, biomarker development, and the investment in more sophisticated clinical trial designs.

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A soluble activin type IIB receptor improves function in a mouse model of amyotrophic lateral sclerosis

Cited by 74 publications

References 33 publications

Inhibiting myostatin reverses muscle fibrosis through apoptosis

Inhibiting myostatin reverses muscle fibrosis through apoptosis

Association of the K153R polymorphism in the myostatin gene and extreme longevity

Therapeutic targeting ofALSpathways: Refocusing an incomplete picture

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