Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function

Tamar E Sztal, Mo Zhao, Caitlin Williams, Viola Oorschot, Adam C Parslow, Aminah Giousoh, Michaela Yuen, Thomas E Hall, Adam Costin, Georg Ramm, Phillip I Bird, Elisabeth M Busch-Nentwich, Derek L Stemple, Peter D Currie, Sandra T Cooper, Nigel G Laing, Kristen J Nowak, Robert J Bryson-Richardson

Research output: Contribution to journalArticleResearchpeer-review

17 Citations (Scopus)

Abstract

Nemaline myopathy is characterized by muscle weakness and the presence of rod-like (nemaline) bodies. The genetic etiology of nemaline myopathy is becoming increasingly understood with mutations in ten genes now known to cause the disease. Despite this, the mechanism by which skeletal muscle weakness occurs remains elusive, with previous studies showing no correlation between the frequency of nemaline bodies and disease severity. To investigate the formation of nemaline bodies and their role in pathogenesis, we generated overexpression and loss-of-function zebrafish models for skeletal muscle ?-actin (ACTA1) and nebulin (NEB). We identify three distinct types of nemaline bodies and visualize their formation in vivo, demonstrating these nemaline bodies not only exhibit different subcellular origins, but also have distinct pathological consequences within the skeletal muscle. One subtype is highly dynamic and upon breakdown leads to the accumulation of cytoplasmic actin contributing to muscle weakness. Examination of a Neb-deficient model suggests this mechanism may be common in nemaline myopathy. Another subtype results from a reduction of actin and forms a more stable cytoplasmic body. In contrast, the final type originates at the Z-disk and is associated with myofibrillar disorganization. Analysis of zebrafish and muscle biopsies from ACTA1 nemaline myopathy patients demonstrates that nemaline bodies also possess a different protein signature. In addition, we show that the ACTA1D286G mutation causes impaired actin incorporation and localization in the sarcomere. Together these data provide a novel examination of nemaline body origins and dynamics in vivo and identifies pathological changes that correlate with muscle weakness.
Original languageEnglish
Pages (from-to)389-406
Number of pages18
JournalActa Neuropathologica
Volume130
Issue number3
DOIs
Publication statusPublished - 2015

Keywords

  • Nemaline
  • Myopathy
  • Zebrafish
  • Actin
  • Protein aggregation

Cite this

Sztal, Tamar E ; Zhao, Mo ; Williams, Caitlin ; Oorschot, Viola ; Parslow, Adam C ; Giousoh, Aminah ; Yuen, Michaela ; Hall, Thomas E ; Costin, Adam ; Ramm, Georg ; Bird, Phillip I ; Busch-Nentwich, Elisabeth M ; Stemple, Derek L ; Currie, Peter D ; Cooper, Sandra T ; Laing, Nigel G ; Nowak, Kristen J ; Bryson-Richardson, Robert J. / Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function. In: Acta Neuropathologica. 2015 ; Vol. 130, No. 3. pp. 389-406.
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abstract = "Nemaline myopathy is characterized by muscle weakness and the presence of rod-like (nemaline) bodies. The genetic etiology of nemaline myopathy is becoming increasingly understood with mutations in ten genes now known to cause the disease. Despite this, the mechanism by which skeletal muscle weakness occurs remains elusive, with previous studies showing no correlation between the frequency of nemaline bodies and disease severity. To investigate the formation of nemaline bodies and their role in pathogenesis, we generated overexpression and loss-of-function zebrafish models for skeletal muscle ?-actin (ACTA1) and nebulin (NEB). We identify three distinct types of nemaline bodies and visualize their formation in vivo, demonstrating these nemaline bodies not only exhibit different subcellular origins, but also have distinct pathological consequences within the skeletal muscle. One subtype is highly dynamic and upon breakdown leads to the accumulation of cytoplasmic actin contributing to muscle weakness. Examination of a Neb-deficient model suggests this mechanism may be common in nemaline myopathy. Another subtype results from a reduction of actin and forms a more stable cytoplasmic body. In contrast, the final type originates at the Z-disk and is associated with myofibrillar disorganization. Analysis of zebrafish and muscle biopsies from ACTA1 nemaline myopathy patients demonstrates that nemaline bodies also possess a different protein signature. In addition, we show that the ACTA1D286G mutation causes impaired actin incorporation and localization in the sarcomere. Together these data provide a novel examination of nemaline body origins and dynamics in vivo and identifies pathological changes that correlate with muscle weakness.",
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author = "Sztal, {Tamar E} and Mo Zhao and Caitlin Williams and Viola Oorschot and Parslow, {Adam C} and Aminah Giousoh and Michaela Yuen and Hall, {Thomas E} and Adam Costin and Georg Ramm and Bird, {Phillip I} and Busch-Nentwich, {Elisabeth M} and Stemple, {Derek L} and Currie, {Peter D} and Cooper, {Sandra T} and Laing, {Nigel G} and Nowak, {Kristen J} and Bryson-Richardson, {Robert J}",
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Sztal, TE, Zhao, M, Williams, C, Oorschot, V, Parslow, AC, Giousoh, A, Yuen, M, Hall, TE, Costin, A, Ramm, G, Bird, PI, Busch-Nentwich, EM, Stemple, DL, Currie, PD, Cooper, ST, Laing, NG, Nowak, KJ & Bryson-Richardson, RJ 2015, 'Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function', Acta Neuropathologica, vol. 130, no. 3, pp. 389-406. https://doi.org/10.1007/s00401-015-1430-3

Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function. / Sztal, Tamar E; Zhao, Mo; Williams, Caitlin; Oorschot, Viola; Parslow, Adam C; Giousoh, Aminah; Yuen, Michaela; Hall, Thomas E; Costin, Adam; Ramm, Georg; Bird, Phillip I; Busch-Nentwich, Elisabeth M; Stemple, Derek L; Currie, Peter D; Cooper, Sandra T; Laing, Nigel G; Nowak, Kristen J; Bryson-Richardson, Robert J.

In: Acta Neuropathologica, Vol. 130, No. 3, 2015, p. 389-406.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Zebrafish models for nemaline myopathy reveal a spectrum of nemaline bodies contributing to reduced muscle function

AU - Sztal, Tamar E

AU - Zhao, Mo

AU - Williams, Caitlin

AU - Oorschot, Viola

AU - Parslow, Adam C

AU - Giousoh, Aminah

AU - Yuen, Michaela

AU - Hall, Thomas E

AU - Costin, Adam

AU - Ramm, Georg

AU - Bird, Phillip I

AU - Busch-Nentwich, Elisabeth M

AU - Stemple, Derek L

AU - Currie, Peter D

AU - Cooper, Sandra T

AU - Laing, Nigel G

AU - Nowak, Kristen J

AU - Bryson-Richardson, Robert J

PY - 2015

Y1 - 2015

N2 - Nemaline myopathy is characterized by muscle weakness and the presence of rod-like (nemaline) bodies. The genetic etiology of nemaline myopathy is becoming increasingly understood with mutations in ten genes now known to cause the disease. Despite this, the mechanism by which skeletal muscle weakness occurs remains elusive, with previous studies showing no correlation between the frequency of nemaline bodies and disease severity. To investigate the formation of nemaline bodies and their role in pathogenesis, we generated overexpression and loss-of-function zebrafish models for skeletal muscle ?-actin (ACTA1) and nebulin (NEB). We identify three distinct types of nemaline bodies and visualize their formation in vivo, demonstrating these nemaline bodies not only exhibit different subcellular origins, but also have distinct pathological consequences within the skeletal muscle. One subtype is highly dynamic and upon breakdown leads to the accumulation of cytoplasmic actin contributing to muscle weakness. Examination of a Neb-deficient model suggests this mechanism may be common in nemaline myopathy. Another subtype results from a reduction of actin and forms a more stable cytoplasmic body. In contrast, the final type originates at the Z-disk and is associated with myofibrillar disorganization. Analysis of zebrafish and muscle biopsies from ACTA1 nemaline myopathy patients demonstrates that nemaline bodies also possess a different protein signature. In addition, we show that the ACTA1D286G mutation causes impaired actin incorporation and localization in the sarcomere. Together these data provide a novel examination of nemaline body origins and dynamics in vivo and identifies pathological changes that correlate with muscle weakness.

AB - Nemaline myopathy is characterized by muscle weakness and the presence of rod-like (nemaline) bodies. The genetic etiology of nemaline myopathy is becoming increasingly understood with mutations in ten genes now known to cause the disease. Despite this, the mechanism by which skeletal muscle weakness occurs remains elusive, with previous studies showing no correlation between the frequency of nemaline bodies and disease severity. To investigate the formation of nemaline bodies and their role in pathogenesis, we generated overexpression and loss-of-function zebrafish models for skeletal muscle ?-actin (ACTA1) and nebulin (NEB). We identify three distinct types of nemaline bodies and visualize their formation in vivo, demonstrating these nemaline bodies not only exhibit different subcellular origins, but also have distinct pathological consequences within the skeletal muscle. One subtype is highly dynamic and upon breakdown leads to the accumulation of cytoplasmic actin contributing to muscle weakness. Examination of a Neb-deficient model suggests this mechanism may be common in nemaline myopathy. Another subtype results from a reduction of actin and forms a more stable cytoplasmic body. In contrast, the final type originates at the Z-disk and is associated with myofibrillar disorganization. Analysis of zebrafish and muscle biopsies from ACTA1 nemaline myopathy patients demonstrates that nemaline bodies also possess a different protein signature. In addition, we show that the ACTA1D286G mutation causes impaired actin incorporation and localization in the sarcomere. Together these data provide a novel examination of nemaline body origins and dynamics in vivo and identifies pathological changes that correlate with muscle weakness.

KW - Nemaline

KW - Myopathy

KW - Zebrafish

KW - Actin

KW - Protein aggregation

UR - http://link.springer.com/content/pdf/10.1007%2Fs00401-015-1430-3.pdf

U2 - 10.1007/s00401-015-1430-3

DO - 10.1007/s00401-015-1430-3

M3 - Article

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SP - 389

EP - 406

JO - Acta Neuropathologica

JF - Acta Neuropathologica

SN - 0001-6322

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