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Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle

Lehmann, Susann; Bass, Joseph J.; Barratt, Thomas F.; Ali, Mohammed Z.; Szewczyk, Nathaniel J.


Susann Lehmann

Joseph J. Bass

Thomas F. Barratt

Mohammed Z. Ali

Nathaniel J. Szewczyk


Background: Skeletal muscle is central to locomotion and metabolic homeostasis. The laboratory worm C. elegans has been developed into a genomic model for assessing the genes and signals that regulate muscle development and protein degradation. Past work has identified a receptor tyrosine kinase signalling network that combinatorially controls autophagy, nerve signal to muscle to oppose proteasome based degradation, and extracellular matrix based signals that control calpain and caspase activation. The last two discoveries were enabled by following up results from a functional genomic screen of known regulators of muscle. Recently, a screen of the kinome requirement for muscle homeostasis identified roughly 40% of kinases as required for C. elegans muscle health; 80 have identified human orthologues and 53 are known to be expressed in skeletal muscle. To complement this kinome screen, here we screen most of the phosphatases in C. elegans.
Methods: RNAi was used to knockdown phosphatase encoding genes. Knockdown was first conducted during development with positive results also knocked down only in fully developed adult muscle. Protein homeostasis, mitochondrial structure, and sarcomere structure were assessed using transgenic reporter proteins. Genes identified as being required to prevent protein degradation were also knocked down in conditions that blocked proteasome or autophagic degradation. Genes identified as being required to prevent autophagic degradation were also assessed for autophagic vesicle accumulation using another transgenic reporter. Lastly, bioinformatics were used to look for overlap between kinases and phosphatases required for muscle homeostasis and the prediction that one phosphatase was required to prevent MAPK activation was assessed by Western blot.
Results: A little over half of all phosphatases are each required to prevent abnormal development or maintenance of muscle. 86 of these phosphatase have known human orthologues, 57 of which are known to be expressed in human skeletal muscle. Of the phosphatases required to prevent abnormal muscle protein degradation, roughly half are required to prevent increased autophagy.
Conclusions: A significant portion of both the kinome and phosphatome are required for establishing and maintaining C. elegans muscle health. Autophagy appears to be the mostly commonly triggered form of protein degradation in response to disruption of phosphorylation based signalling. The results from these screens provide measurable phenotypes for analysing the combined contribution of kinases and phosphatases in a multi-cellular organism and suggest new potential regulators of human skeletal muscle for further analysis.


Lehmann, S., Bass, J. J., Barratt, T. F., Ali, M. Z., & Szewczyk, N. J. (2017). Functional phosphatome requirement for protein homeostasis, networked mitochondria, and sarcomere structure in C. elegans muscle. Journal of Cachexia, Sarcopenia and Muscle, 8(4), 660-672.

Journal Article Type Article
Acceptance Date Jan 26, 2017
Online Publication Date May 15, 2017
Publication Date 2017-08
Deposit Date Feb 21, 2017
Publicly Available Date May 15, 2017
Journal Journal of Cachexia, Sarcopenia and Muscle
Print ISSN 2190-5991
Electronic ISSN 2190-6009
Publisher Wiley Open Access
Peer Reviewed Peer Reviewed
Volume 8
Issue 4
Pages 660-672
Keywords Phosphatase; C. elegans; Sarcomere; Proteostasis; Protein degradation; Muscle
Public URL
Publisher URL
Copyright Statement Copyright information regarding this work can be found at the following address:


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