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closeReferee comments: Referee 4 (King-Tung Chin)
Posted by PLOS_ONE_Group on 18 Feb 2008 at 18:44 GMT
Referee 4's review (King-Tung Chin):
In this manuscript, the authors present evidence that the ubiquitin ligase RNF5 is critically involved in muscle physiology as well as ER stress-associated muscular disorders. In particular, RNF5 expression was found to be increased and mislocalized in clinical biopsies of sporadic IBM. This observation was further confirmed in a mouse model of hereditary IBM. In addition, the roles of RNF5 in muscle degeneration/regeneration and ER stress associated muscular pathogenesis (both are traits of IBM) were further substantiated by RNF5 inducible transgenic and knockout mouse models. Generally this paper is well written and the data are clearly presented. It is an important piece of work which generates an animal model that serves as a platform to further the understanding of ER-stress pathways on muscle physiology and pathology. Thus this manuscript is suitable to be published in PLoS ONE after the revision of the manuscript regarding the following points.
It is good to have pictures showing the difference in expression and localization of RNF5 between normal and sIBM muscle biopsies (Fig. 1). However, the authors should make use of all their biopsies samples and perform statistical analysis comparing at least the expression level of RNF5 in normal versus sIBM muscle. One of the ways to do that is by performing Western analysis.
In Fig. 1C panel c & d, it is hard to find the rimmed vacuoles the authors claimed. Can they be indicated more clearly?
Fig. 4G and Fig. S3 should be combined. CD11b-postivie and -negative control should be included to tell the difference between DTg and its control tissues.
On page 12 line 14-17, weak myogenin staining was also observed in control muscle in Fig. 4E. Therefore it is not accurate to say myogenin is not expressed in control tissue.
For Fig. 3 and 5, the authors should state at which stage of doxycyclin treatment the animals were used for the analysis. This will generate more insights into the sequential cellular processes required for the pathogenesis of sIBM.
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N.B. These are the comments made by the referee when reviewing an earlier version of this paper. Prior to publication the manuscript has been revised in light of these comments and to address other editorial requirements.