Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis

Holzbaur, Erika L.F.; Howland, David; Weber, Nicholas; Wallace, Kathleen; She, Yijin; Kwak, Seung; Tchistiakova, Lioudmilla A.; Murphy, Erin; Hinson, Joseph; Karim, Riyez; Tan, Xiang Yang; Kelley, Pamela; McGill, Kevin C.; Williams, Gareth; Hobbs, Carl; Doherty, Patrick; Zaleska, Margaret M.; Pangalos, Menelas N.; Walsh, Frank S.

doi:10.1016/j.nbd.2006.05.009

Cited by 84 publications

(61 citation statements)

References 33 publications

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“…In support of this view, a previous study showed that inhibition of myostatin has little effect on muscle damage in rodent models of ALS (Holzbaur et al, 2006).…”

Section: Roles Of Tgf-␤ In Non-neuronal Cellsmentioning

confidence: 76%

Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy

Katsuno¹,

Adachi²,

Minamiyama³

et al. 2010

J. Neurosci.

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Spinal and bulbar muscular atrophy (SBMA) is a late-onset lower motor neuron disease caused by the expansion of a trinucleotide CAG repeat, which encodes a polyglutamine tract in androgen receptor (AR). Although it is commonly held that the pathogenic polyglutamine proteins accumulate in neurons and thereby induce transcriptional dysregulation, the downstream molecular events have remained elusive. Here, we examined whether TGF-␤ signaling is dysregulated in SBMA. Nuclear translocation of phosphorylated Smad2/3, a key step in TGF-␤ signaling, is suppressed in the spinal motor neurons of male transgenic mice carrying the mutant human AR. A similar finding was also observed in the motor neurons, but not in Purkinje cells, of SBMA patients. The pathogenic AR, the causative protein of SBMA, inhibits the transcription of TGF-␤ receptor type II (T␤RII) via abnormal interactions with NF-Y and p300/CBP-associated factor. Furthermore, overexpression of T␤RII dampens polyglutamine-induced cytotoxicity in a neuroblastoma cell line expressing the pathogenic AR. The present study thus indicates that disruption of TGF-␤ due to the transcriptional dysregulation of T␤RII is associated with polyglutamine-induced motor neuron damage in SBMA.

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“…In support of this view, a previous study showed that inhibition of myostatin has little effect on muscle damage in rodent models of ALS (Holzbaur et al, 2006).…”

Section: Roles Of Tgf-␤ In Non-neuronal Cellsmentioning

confidence: 76%

Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy

Katsuno¹,

Adachi²,

Minamiyama³

et al. 2010

J. Neurosci.

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“…Taken together, these studies suggest that although myostatin inhibition can ameliorate several different types of muscular dystrophy, it is important to choose the proper type of dystrophy and disease stages. One report showed that neurogenic muscle atrophy by amyotrophic lateral sclerosis could be slowed by myostatin inhibition [42].…”

Section: A Muscular Dystrophy and Related Diseasesmentioning

confidence: 99%

Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

et al. 2008

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Abstract. Activin, myostatin and other members of the TGF-β superfamily signal through a combination of type II and type I receptors, both of which are transmembrane serine/threonine kinases. Activin type II receptors, ActRIIA and ActRIIB, are primary ligand binding receptors for activins, nodal, myostatin and GDF11. ActRIIs also bind a subset of bone morphogenetic proteins (BMPs). Type I receptors that form complexes with ActRIIs are dependent on ligands. In the case of activins and nodal, activin receptor-like kinases 4 and 7 (ALK4 and ALK7) are the authentic type I receptors. Myostatin and GDF11 utilize ALK5, although ALK4 could also be activated by these growth factors. ALK4, 5 and 7 are structurally and functionally similar and activate receptor-regulated Smads for TGF-β, Smad2 and 3. BMPs signal through a combination of three type II receptors, BMPRII, ActRIIA, and ActRIIB and four type I receptors, ALK1, 2, 3, and 6. BMPs activate BMP-specific Smads, Smad1, 5 and 8. Smad proteins undergo multimerization with co-mediator Smad, Smad4, and translocated into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. The signal transduction pathway through activin type II receptors, ActRIIA and ActRIIB, with type I receptors is involved in various human diseases. In this review, we discuss the role of signaling through activin receptors as therapeutic targets of intractable neuromuscular diseases, endocrine disorders and cancers.

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“…34 Pharmacological inhibition of myostatin activity in rodents from either myostatin neutralizing antibodies, mutant myostatin propeptides or even decoy myostatin receptor-fusion proteins, results in increased muscle mass and improved muscle function. [37][38][39] As previously reported, a murine antibody termed RK35 was obtained through hybridoma technology. RK35 neutralizes mature myostatin signaling through activin receptor IIB (ActRIIB), and showed promising in vivo results, including slowing of muscle atrophy and grip strength loss in rodent models of ALS.…”

Section: Introductionmentioning

confidence: 99%

“…RK35 neutralizes mature myostatin signaling through activin receptor IIB (ActRIIB), and showed promising in vivo results, including slowing of muscle atrophy and grip strength loss in rodent models of ALS. 38,39 In this work, we initially demonstrate the successful humanization of the anti-myostatin antibody with a traditional CDR grafting approach onto clinically validated germline frameworks. 40 Following the traditional CDR grafting, we explored the further reduction of murine CDR content guided by co-crystal structures of the antibody:antigen complex.…”

Section: Introductionmentioning

confidence: 99%

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

Apgar

Mader

Agostinelli

et al. 2016

mAbs

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Antibodies are an important class of biotherapeutics that offer specificity to their antigen, long half-life, effector function interaction and good manufacturability. The immunogenicity of non-human-derived antibodies, which can be a major limitation to development, has been partially overcome by humanization through complementarity-determining region (CDR) grafting onto human acceptor frameworks. The retention of foreign content in the CDR regions, however, is still a potential immunogenic liability. Here, we describe the humanization of an anti-myostatin antibody utilizing a 2-step process of traditional CDR-grafting onto a human acceptor framework, followed by a structure-guided approach to further reduce the murine content of CDR-grafted antibodies. To accomplish this, we solved the co-crystal structures of myostatin with the chimeric (Protein Databank (PDB) id 5F3B) and CDR-grafted antimyostatin antibody (PDB id 5F3H), allowing us to computationally predict the structurally important CDR residues as well as those making significant contacts with the antigen. Structure-based rational design enabled further germlining of the CDR-grafted antibody, reducing the murine content of the antibody without affecting antigen binding. The overall "humanness" was increased for both the light and heavy chain variable regions.

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Myostatin inhibition slows muscle atrophy in rodent models of amyotrophic lateral sclerosis

Cited by 84 publications

References 33 publications

Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy

Disrupted Transforming Growth Factor-β Signaling in Spinal and Bulbar Muscular Atrophy

Signal Transduction Pathway through Activin Receptors as a Therapeutic Target of Musculoskeletal Diseases and Cancer

Beyond CDR-grafting: Structure-guided humanization of framework and CDR regions of an anti-myostatin antibody

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