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 (Smyd1 b) is known to play a crucial role in myofibrillogenesis by functionally interacting with the myosin chaperones Unc45b and Hsp9Oa1. In zebrafish, Smydl b, Unc45b and Hsp90c0 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 smydl gene, termed smydla. Morpholino- and CRISPR/Cas9-mediated knockdown of smydla led to significant perturbations in sarcomere structure resulting in decreased cardiac as well as skeletal muscle function. Similar to Smydl b, we found Smydla to localize to the sarcomeric M-band in skeletal and cardiac muscles. Overexpression of smydla efficiently compensated for the loss of Smydl b in flatline (fla) mutant zebrafish embryos, rescued the myopathic phenotype and suppressed the MMR in Smydl b-deficient embryos, suggesting overlapping functions of both Smydl paralogs. Interestingly, Smydla is not transcriptionally activated in Smydlb-deficient fib mutants, demonstrating lack of genetic compensation despite the functional redundancy of both zebrafish Smydl paralogs. (C) 2018 The Authors. Published by Elsevier Inc.