Comparative plasma proteomics in muscle atrophy during cancer-cachexia and disuse: The search for atrokines.

Abstract

Skeletal muscle atrophy is common across a variety of pathologies. Underlying mechanisms of atrophy differ between pathologies, and in many conditions, circulating factors are tied to muscle atrophy. Therefore, we sought to identify alterations to the plasma proteome across divergent forms of muscle atrophy, disuse and cancer cachexia, as potential mediators of atrophy. C57BL6/J mice were assigned to Lewis Lung Carcinoma (LLC)-induced cachexia, disuse by hindlimb unloading (HU), or control (CON). Plasma samples were submitted for discovery proteomics and targets of interest confirmed by immunoblot. Considerably more peptides were altered in plasma from LLC (91) than HU (9) as compared to CON. Five total proteins were similarly modulated in HU and LLC compared to CON, none reached criteria for differential expression. Serum Amyloid A1 (SAA) was 4 and 6 Log2 FC greater in LLC than CON or HU, respectively, confirmed by immunoblot. Recent reports suggest SAA is sufficient to induce atrophy via TLR. Therefore, we assessed TLR2,4, and IL-6 mRNAs in hindlimb muscles. TLR mRNAs were not altered, suggesting SAA effects on atrophy during LLC are independent of TLR signaling. However, we noted > 6-fold induction of IL-6 in soleus of HU mice, despite minimal shift in the plasma proteome, indicating potential localized inflammation in atrophying muscle. Furthermore, paraoxonase 1 (PON1) was highly repressed in LLC mice and largely undetectable by immunoblot in this group. Our data suggest SAA and PON1 as potential novel atrokines for cancer cachexia and indicate localized inflammation in atrophying muscles independent of the plasma proteome.

• Authors: Seongkyun Lim, Kirsten R Dunlap, Megan E Rosa-Caldwell, Wesley S Haynie, Lisa T Jansen, Tyrone A Washington, Nicholas P Greene
• Journal: Physiological reports (Physiol Rep) Vol. 8 Issue 19 Pg. e14608 (10 2020) ISSN: 2051-817X [Electronic] United States
• PMID: 33063952 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © 2020 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Topics

• Animals
• Cachexia (metabolism, pathology)
• Female
• Hindlimb Suspension (physiology)
• Male
• Mice, Inbred C57BL
• Mice, Transgenic
• Muscle, Skeletal (metabolism)
• Muscular Atrophy (metabolism)
• Neoplasms (drug therapy, metabolism, pathology)
• Proteomics