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

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 - Acta Neuropathol. (2015)

Bottom Line: 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.In addition, we show that the ACTA1(D286G) mutation causes impaired actin incorporation and localization in the sarcomere.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Monash University, Melbourne, VIC, Australia.

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 α-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 ACTA1(D286G) 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.

No MeSH data available.


Related in: MedlinePlus

Nemaline bodies form in skeletal muscle in Tg(ACTA1D286G-eGFP)high zebrafish. Nemaline bodies were detected in a skeletal muscle (arrowheads) and pectoral fins (arrow) (i and ii overlaid with brightfield), b heart (arrowheads) (i and ii overlaid with brightfield), c facial muscles (arrowheads) (i and ii overlaid with brightfield) and d ocular muscles (arrowheads; i and overlaid with ii brightfield)
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Fig1: Nemaline bodies form in skeletal muscle in Tg(ACTA1D286G-eGFP)high zebrafish. Nemaline bodies were detected in a skeletal muscle (arrowheads) and pectoral fins (arrow) (i and ii overlaid with brightfield), b heart (arrowheads) (i and ii overlaid with brightfield), c facial muscles (arrowheads) (i and ii overlaid with brightfield) and d ocular muscles (arrowheads; i and overlaid with ii brightfield)

Mentions: We created a conditional transgenic zebrafish model for ACTA1 nemaline myopathy, Tg(ACTA1D286G-eGFP) that expresses human ACTA1D286G in skeletal muscles. The Tg(ACTA1D286G-eGFP)high fish recapitulate hallmark pathological features of the disease with the presence of nemaline bodies in skeletal muscles at 48 and 72 hpf (Supplementary Figure S1). In addition to the trunk musculature, other striated muscles such as the facial, heart, and ocular muscles also contained numerous nemaline bodies (Fig. 1). At 72 hpf, we observed aggregates at the myosepta. These aggregates differ in appearance to the earlier-forming nemaline bodies, having a globular appearance rather than a clear and defined rod shape (Supplementary Figure S1).Fig. 1


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

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 - Acta Neuropathol. (2015)

Nemaline bodies form in skeletal muscle in Tg(ACTA1D286G-eGFP)high zebrafish. Nemaline bodies were detected in a skeletal muscle (arrowheads) and pectoral fins (arrow) (i and ii overlaid with brightfield), b heart (arrowheads) (i and ii overlaid with brightfield), c facial muscles (arrowheads) (i and ii overlaid with brightfield) and d ocular muscles (arrowheads; i and overlaid with ii brightfield)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4541704&req=5

Fig1: Nemaline bodies form in skeletal muscle in Tg(ACTA1D286G-eGFP)high zebrafish. Nemaline bodies were detected in a skeletal muscle (arrowheads) and pectoral fins (arrow) (i and ii overlaid with brightfield), b heart (arrowheads) (i and ii overlaid with brightfield), c facial muscles (arrowheads) (i and ii overlaid with brightfield) and d ocular muscles (arrowheads; i and overlaid with ii brightfield)
Mentions: We created a conditional transgenic zebrafish model for ACTA1 nemaline myopathy, Tg(ACTA1D286G-eGFP) that expresses human ACTA1D286G in skeletal muscles. The Tg(ACTA1D286G-eGFP)high fish recapitulate hallmark pathological features of the disease with the presence of nemaline bodies in skeletal muscles at 48 and 72 hpf (Supplementary Figure S1). In addition to the trunk musculature, other striated muscles such as the facial, heart, and ocular muscles also contained numerous nemaline bodies (Fig. 1). At 72 hpf, we observed aggregates at the myosepta. These aggregates differ in appearance to the earlier-forming nemaline bodies, having a globular appearance rather than a clear and defined rod shape (Supplementary Figure S1).Fig. 1

Bottom Line: 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.In addition, we show that the ACTA1(D286G) mutation causes impaired actin incorporation and localization in the sarcomere.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Monash University, Melbourne, VIC, Australia.

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 α-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 ACTA1(D286G) 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.

No MeSH data available.


Related in: MedlinePlus