The culprit behind chemotherapy-induced muscle atrophy
October 27, 2014
October's featured paper is called "Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle," published in PLoS One by a team from the Marks Lab.
You've been diagnosed with cancer. Chemotherapy and the accompanying myriad of side effects have begun. While the nausea and hair loss were expected, a sudden and extreme loss of muscle mass was not.
Cachexia, weight loss marked by significant loss of skeletal muscle, is a progressive syndrome that complicates many chronic or severe diseases. It is estimated that cachexia affects more than half of all cancer patients and is directly responsible for 20 percent of cancer deaths.
While research has investigated the mechanisms by which cancer produces muscle atrophy, our understanding of how cancer treatments contribute to the development of cachexia is less well understood.
"Chemotherapy is well known to be complicated by cachexia, and this can be a debilitating aspect of cancer therapy," said Eric Orwoll, M.D., associate dean for clinical research. "This month's featured paper uses a series of well-designed experiments to demonstrate that cachexia is mediated by inflammation but is also dependent on the glucocorticoid receptor in muscle."
The chemotherapy connection
"Previous research had shown that cytotoxic chemotherapy induces numerous metabolic changes, including atrophy of skeletal muscle," said Daniel Marks, M.D., Ph.D., professor of pediatrics in the OHSU School of Medicine, with a focus on endocrinology. "Additionally, chemotherapy induces significant systemic inflammation. Our study directly investigated the mechanism of chemotherapy-induced muscle atrophy."
"We previously demonstrated that skeletal muscle atrophy depends on activation of glucocorticoid signaling in response to acute bacterial infection," said lead author Theodore Braun, M.D. '14, Ph.D. '14 (pictured left), now a resident in internal medicine at University of Washington. "Using mice with a conditional deletion of the glucocorticoid receptor in skeletal muscle allowed us to investigate the involvement of glucocorticoid signaling in muscle atrophy in response to chemotherapy."
Dr. Braun and members of the Marks laboratory were able to demonstrate that a mouse model lacking the glucocorticoid receptor was protected from muscle atrophy in response to chemotherapy administration.
Moreover, they were able to show that glucocorticoids are required for the induction of a destructive metabolic response, primarily through the increased expression of genes involved with proteasomal degradation of skeletal muscle.
"Drs. Braun and Marks were able to execute experiments that show that cachexia is mediated by inflammation and is dependent on the glucocorticoid receptor in muscle," said Dr. Orwoll. "Importantly, this opens avenues for potential therapies to prevent muscle wasting during chemotherapy."
Treatment of cachexia will greatly improve curative chemotherapy, as atrophy of skeletal muscle contributes significantly to declining patient health. "Understanding the mechanistic underpinnings of chemotherapy-induced muscle atrophy will allow for the rational design of pharmacotherapy for this devastating complication of cancer treatment," said Dr. Braun.
"Future work will focus on the development of selective antagonists of the glucocorticoid receptor in skeletal muscle," added Dr. Marks.
Through this study and future research, treatment across a wide variety of cancers may become more effective as the complications of cachexia are reduced or eliminated.
Muscle atrophy in response to cytotoxic chemotherapy is dependent on intact glucocorticoid signaling in skeletal muscle.
Theodore P. Braun, Marek Szumowski, Peter R. Levasseur, Aaron J. Grossberg, XinXia Zhu, Anupriya Agarwal, Daniel L. Marks
PLoS One. 2014 Sep 25;9(9):e106489. doi: 10.1371/journal.pone.0106489. eCollection 2014.
MORE PUBLISHED PAPERS
Top photo, from left to right: XinXia Zhu, Daniel Marks
Botton photo: Theodore Braun
About the School of Medicine Paper of the Month
The School of Medicine newsletter spotlights a recently published faculty research paper in each issue. The goals are to highlight the great research happening at OHSU and to share this information across departments, institutes and disciplines. The monthly paper summary is selected by Senior Associate Dean for Research Mary Stenzel-Poore, Ph.D., Associate Dean for Clinical Science Eric Orwoll, M.D., and Assistant Dean for Basic Research Mary Heinricher, Ph.D.