Ccn6 Is Required for Mitochondrial Integrity and Skeletal Muscle Function in Zebrafish.

Archya Sengupta,Deepesh Kumar Padhan,Malini Sen,Ananya Ganguly

doi:10.3389/fcell.2021.627409

Archya Sengupta, Deepesh Kumar Padhan + Show 2 more

Open Access

https://doi.org/10.3389/fcell.2021.627409

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Abstract

Mutations in the CCN6 (WISP3) gene are linked with a debilitating musculoskeletal disorder, termed progressive pseudorheumatoid dysplasia (PPRD). Yet, the functional significance of CCN6 in the musculoskeletal system remains unclear. Using zebrafish as a model organism, we demonstrated that zebrafish Ccn6 is present partly as a component of mitochondrial respiratory complexes in the skeletal muscle of zebrafish. Morpholino-mediated depletion of Ccn6 in the skeletal muscle leads to a significant reduction in mitochondrial respiratory complex assembly and activity, which correlates with loss of muscle mitochondrial abundance. These mitochondrial deficiencies are associated with notable architectural and functional anomalies in the zebrafish muscle. Taken together, our results indicate that Ccn6-mediated regulation of mitochondrial respiratory complex assembly/activity and mitochondrial integrity is important for the maintenance of skeletal muscle structure and function in zebrafish. Furthermore, this study suggests that defects related to mitochondrial respiratory complex assembly/activity and integrity could be an underlying cause of muscle weakness and a failed musculoskeletal system in PPRD.

Highlights

CCN6 (WISP3), a CCN (Cyr61, CTGF, NOV) family member, is a multi-domain protein that is expressed in most cells of mesenchymal origin
Our results indicate that defects in the mitochondrial respiratory complex assembly/activity and loss of mitochondrial integrity may constitute an underlying cause of muscle weakness associated with progressive pseudorheumatoid dysplasia (PPRD)
Based on studies in human chondrocyte lines demonstrating that CCN6 localizes to the mitochondria and regulates mitochondrial respiratory complex assembly and activity, we intended to validate the function of CCN6 at the organism level

Summary

Introduction

CCN6 (WISP3), a CCN (Cyr, CTGF, NOV) family member, is a multi-domain protein that is expressed in most cells of mesenchymal origin. Mutations in the CCN6 gene, which span across the entire length of the protein coding sequence, are linked with a musculoskeletal disorder termed progressive pseudorheumatoid dysplasia (PPRD) (Hurvitz et al, 1999). Progressive pseudorheumatoid dysplasia, an incurable debilitating disorder, is characterized by loss of cartilage, muscle weakness, and irregular bone growth especially in the joints (Hurvitz et al, 1999; Dalal et al, 2012; Sun et al, 2012; Ekbote et al, 2013; Yang et al, 2013; Liu et al, 2015; Luo et al, 2015; Chouery et al, 2017; Alawbathani et al, 2018; Shahi et al, 2020).

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