Klhl41b orchestrates sarcomere assembly and growth to drive skeletal muscle hypertrophy in vivo.
5 affiliations
- 1Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.
- 2Department of Biological Sciences, University of Massachusetts Lowell, Lowell, MA, USA.
- 3Division of Genetics and Genomics, Boston Children's Hospital, Boston, MA, USA.
- 4Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, USA.
- 5Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
Abstract
Background
Nemaline myopathy (NM) is a clinically and genetically heterogeneous disease caused by mutations in sarcomere-associated genes, with congenital forms representing the most severe end of the spectrum. Recessive mutations in KLHL41 underlie a severe congenital NM characterized by sarcomeric disorganization and impaired muscle growth. The in vivo mechanisms by which KLHL41 governs sarcomere assembly and growth remain poorly understood.Methods
We generated zebrafish models of KLHL41 deficiency by the CRISPR-Cas9 approach to examine the temporal and molecular basis of sarcomere assembly defects in NM. The phenotypic and physiological characterization of skeletal muscle defects was investigated by birefringence, spontaneous coiling, spontaneous swimming behavior, and force generation assays. Structural analyses by electron microscopy and immunofluorescence assessed myofibril organization and sarcomere structures across developmental time points. Quantitative proteomics and biochemical assays were performed to identify perturbations in sarcomeric proteins and associated molecular pathways.Results
We show that Klhl41b is essential for the formation and organization of sarcomeres, supporting both radial and longitudinal muscle growth. Loss of Klhl41b resulted in reduced sarcomere size, defective sarcomere assembly followed by progressive destabilization of sarcomeres, nemaline body formation, and reduced muscle function. Proteomic analysis in Klhl41b-deficient zebrafish revealed reduced abundance of the sarcomeric troponin complex proteins, altered abundance of components of the translational machinery, and increased abundance of components of atrophy-associated pathways.Conclusions
These data show that Klhl41b is required for sarcomere assembly and growth, and its deficiency drives a cascade of structural and molecular changes underlying skeletal muscle hypotrophy and NM pathology. These findings advance our understanding of disease mechanisms and may inform targeted therapeutic strategies to restore sarcomere integrity and muscle function.
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BibTeX
@article{han2026klhl41b,
title = {{Klhl41b orchestrates sarcomere assembly and growth to drive skeletal muscle hypertrophy in vivo.}},
author = {Hyewon Han and Grace R Tate and Janet Shi and Alfredo H Bongiorno and Arian Mansur and Jeffrey Widrick and Sehajpreet Gill and Esmat Karimi and Henk Granzier and Jeffrey R Moore and Vandana A Gupta},
journal = {Skeletal muscle},
year = {2026},
month = oct,
doi = {10.1186/s13395-026-00453-2},
url = {https://europepmc.org/article/MED/42870309},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Klhl41b orchestrates sarcomere assembly and growth to drive skeletal muscle hypertrophy in vivo.
AU - Hyewon Han
AU - Grace R Tate
AU - Janet Shi
AU - Alfredo H Bongiorno
AU - Arian Mansur
AU - Jeffrey Widrick
AU - Sehajpreet Gill
AU - Esmat Karimi
AU - Henk Granzier
AU - Jeffrey R Moore
AU - Vandana A Gupta
PY - 2026
DA - 2026/10/08
JO - Skeletal muscle
DO - 10.1186/s13395-026-00453-2
UR - https://europepmc.org/article/MED/42870309
AB - Background Nemaline myopathy (NM) is a clinically and genetically heterogeneous disease caused by mutations in sarcomere-associated genes, with congenital forms representing the most severe end of the spectrum. Recessive mutations in KLHL41 underlie a severe congenital NM characterized by sarcomeric disorganization and impaired muscle growth. The in vivo mechanisms by which KLHL41 governs sarcomere assembly and growth remain poorly understood.Methods We generated zebrafish models of KLHL41 deficiency by the CRISPR-Cas9 approach to examine the temporal and molecular basis of sarcomere assembly defects in NM. The phenotypic and physiological characterization of skeletal muscle defects was investigated by birefringence, spontaneous coiling, spontaneous swimming behavior, and force generation assays. Structural analyses by electron microscopy and immunofluorescence assessed myofibril organization and sarcomere structures across developmental time points. Quantitative proteomics and biochemical assays were performed to identify perturbations in sarcomeric proteins and associated molecular pathways.Results We show that Klhl41b is essential for the formation and organization of sarcomeres, supporting both radial and longitudinal muscle growth. Loss of Klhl41b resulted in reduced sarcomere size, defective sarcomere assembly followed by progressive destabilization of sarcomeres, nemaline body formation, and reduced muscle function. Proteomic analysis in Klhl41b-deficient zebrafish revealed reduced abundance of the sarcomeric troponin complex proteins, altered abundance of components of the translational machinery, and increased abundance of components of atrophy-associated pathways.Conclusions These data show that Klhl41b is required for sarcomere assembly and growth, and its deficiency drives a cascade of structural and molecular changes underlying skeletal muscle hypotrophy and NM pathology. These findings advance our understanding of disease mechanisms and may inform targeted therapeutic strategies to restore sarcomere integrity and muscle function.
SN - 2044-5040
ER -