Referee 1's Review:

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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.
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Summary: This study investigates the mechanism involved in the observation that oxidative skeletal muscles are more resistant to cachexia than glycolytic muscles. The investigators observe that oxidative muscle is more resistant to cachexia (as measured by MuRF1 and MAFBx/Atrogin-1 mRNA) due to its enhanced NO production and anti-oxidant protein expression.

This manuscript does a nice job of detailing the mechanism of differences in anti-oxidant and reactive oxygen specifics in oxidative skeletal muscle compared to glycolytic muscle. However, there are several shortcomings that need to be addressed before the manuscript might be acceptable for publication. These are detailed as follows:

Major points:
1. There is no evidence that cachexia is actually present in either the in vivo and in vitro experiments at the 24 hour time point outlined in the manuscript after LPS challenge. The authors use MAFBx/Atrogin-1 and MuRF1 as early markers of cachexia. While these markers do indeed mediate cachexia, the relationship between atrogene expression and cachexia has not been made.

This manuscript needs to quantify that cachexia has occurred both in vivo (i.e. present muscles weight/body weight) and in vitro (i.e. surface area of cells). If the authors could do that, they may be demonstrating protective mechanisms in early cachexia. Alternatively, they could demonstrate that similar mechanisms are at work at a later time point that cachexia could be documented in the specific cells they are measuring.

2. The muscle cross section of muscle in Figure 2F demonstrates both a control and a LPS treated muscles (SO and WV). The cross sectional areas of the LPS treated mice appear to be bigger than the controls, consistent with muscle mass increases (exactly opposite of what is expected). Are the mice age and litter matched? Can you please calculate the myocyte cross sections to detect if cachexia is occurring in LPS treated mice?

3. The authors use an undifferentiated myoblast cell line to delineate mechanisms in differentiated skeletal muscle. How is iNos and Sod3 affected in SO and WV muscle?

Minor points:

1. Atrogin-1 is misspelled in Figure 1D.

2. The authors should describe what type of LPS was used (Strain of bacteria), and indicate if there was any morbidity or mortality involved.

3. Could the authors comment on whether there is any affect on protein synthesis in these muscle types? Couldn't the differences in "cachexia" be due to difference affect on protein synthesis, and not just affects on the degradation by MuRF1 and Atrogin-1? MuRF1 may regulate protein synthesis in addition to degrading the sarcomere (EMBO J. 2008 Jan 23;27(2):350-60. Epub 2007 Dec 20.).