Loss of zebrafish Smyd1a interferes with myofibrillar integrity without triggering the misfolded myosin response

Journal Article · Thu Feb 15 04:00:00 EST 2018 · Biochemical and Biophysical Research Communications

DOI:https://doi.org/10.1016/J.BBRC.2018.01.060· OSTI ID:23127414

Paone, Christoph; Rudeck, Steven ^[1]; Etard, Christelle; Strähle, Uwe ^[2]; Rottbauer, Wolfgang ^[3]; Just, Steffen ^[1]

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1. Molecular Cardiology, Department of Inner Medicine II, University of Ulm, Ulm (Germany)
2. Institute of Toxicology and Genetics (ITG), Karlsruhe Institute of Technology (KIT), Eggenstein-Leopoldshafen (Germany)
3. Department of Inner Medicine II, University of Ulm, Ulm (Germany)

Highlights: • Smyd1a is expressed in fast-twitch skeletal as well as heart muscle. • Loss-of smyd1b can be compensated by overexpression of smyd1a. • Smyd1a and smyd1b are part of different transcriptional regulatory mechanisms. Sarcomeric protein turnover needs to be tightly balanced to assure proper assembly and renewal of sarcomeric units within muscle tissues. The mechanisms regulating these fundamental processes are only poorly understood, but of great clinical importance since many cardiac and skeletal muscle diseases are associated with defective sarcomeric organization. The SET- and MYND domain containing protein 1b (Smyd1b) is known to play a crucial role in myofibrillogenesis by functionally interacting with the myosin chaperones Unc45b and Hsp90α1. In zebrafish, Smyd1b, Unc45b and Hsp90α1 are part of the misfolded myosin response (MMR), a regulatory transcriptional response that is activated by disturbed myosin homeostasis. Genome duplication in zebrafish led to a second smyd1 gene, termed smyd1a. Morpholino- and CRISPR/Cas9-mediated knockdown of smyd1a led to significant perturbations in sarcomere structure resulting in decreased cardiac as well as skeletal muscle function. Similar to Smyd1b, we found Smyd1a to localize to the sarcomeric M-band in skeletal and cardiac muscles. Overexpression of smyd1a efficiently compensated for the loss of Smyd1b in flatline (fla) mutant zebrafish embryos, rescued the myopathic phenotype and suppressed the MMR in Smyd1b-deficient embryos, suggesting overlapping functions of both Smyd1 paralogs. Interestingly, Smyd1a is not transcriptionally activated in Smyd1b-deficient fla mutants, demonstrating lack of genetic compensation despite the functional redundancy of both zebrafish Smyd1 paralogs.

• OSTI ID: 23127414
• Journal Information: Biochemical and Biophysical Research Communications, Journal Name: Biochemical and Biophysical Research Communications Journal Issue: 2 Vol. 496; ISSN 0006-291X; ISSN BBRCA9
• Country of Publication: United States
• Language: English

Related Subjects

60 APPLIED LIFE SCIENCES
DISEASES
EMBRYOS
GENETICS
HEART
HOMEOSTASIS
MUSCLES
MYOSIN