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IL‐6 inhibition attenuates activation of ubiquitin proteasome‐dependent degradation in cachectic muscle
Author(s) -
White James,
Puppa Melissa,
Sato Shuichi,
Baynes John,
Welle Steven,
Carson James
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.1105.12
Subject(s) - cachexia , wasting , chemistry , ubiquitin , endocrinology , medicine , foxo3 , muscle atrophy , myostatin , proteasome , autophagy , cancer , signal transduction , skeletal muscle , biochemistry , protein kinase b , apoptosis , gene
The ubiquitin proteasomal (Ub) pathway is a dominant proteolytic pathway during cachexia‐induced muscle wasting. We have previously shown that IL‐6 can regulate muscle wasting and activate the Ub pathway in the ApcMin/+ mouse, a model of colorectal cancer. The purpose of this study was to determine if inhibition of IL‐6 through administration of an IL‐6 receptor antibody (IL6Ab) can attenuate the Ub pathway after cachexia has been initiated. Ub activation in the gastrocnemius was determined in wild‐type (Wt) and ApcMin/+ mice treated with the IL6Ab or PBS control from 16 to 18 weeks of age, a key time point in the development of body weight loss in ApcMin/+ mice. Administration of the IL6Ab attenuated the loss of body weight in ApcMin/+ mice from 15 to 7%. At 18 weeks of age, proteasomal subunits C2 and C7 were increased by 2 and 3.5 fold in PBS treated ApcMin/+ mice while IL6Ab treatment reduced expression by 32 and 37%. PBS treated ApcMin/+ mice showed a 2.5 fold increase in atrogin‐1 which was decreased to 34% by IL6Ab treatment. In conjunction with the changes observed with atrogin‐1, PBS treated ApcMin/+ mice showed a 65% reduction in phospho FOXO3 which was increased by 65% when treated with the IL6Ab. IL6Ab treatment has no effect on Wt mice for any variables. These data show muscle Ub activation can be attenuated by inhibition of IL‐6 which blocks the progression of cachexia in ApcMin/+ mice. Funded by R01CA121249‐01A2