Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function

Introduction. Doxorubicin (DOX) is widely used as a chemotherapy drug for cancer. However, it is known to affect negatively skeletal muscle mass and function, which can expose to other diseases and decrease survival rate. Presently, there are no accepted drugs for muscle wasting, but myostatin and a...

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Main Author: Poikonen, Aino
Other Authors: Liikuntatieteellinen tiedekunta, Faculty of Sport and Health Sciences, Liikuntabiologian laitos, Department of Biology of Physical Activity, University of Jyväskylä, Jyväskylän yliopisto
Format: Master's thesis
Language:eng
Published: 2016
Subjects:
Online Access: https://jyx.jyu.fi/handle/123456789/50573
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author Poikonen, Aino
author2 Liikuntatieteellinen tiedekunta Faculty of Sport and Health Sciences Liikuntabiologian laitos Department of Biology of Physical Activity University of Jyväskylä Jyväskylän yliopisto
author_facet Poikonen, Aino Liikuntatieteellinen tiedekunta Faculty of Sport and Health Sciences Liikuntabiologian laitos Department of Biology of Physical Activity University of Jyväskylä Jyväskylän yliopisto Poikonen, Aino Liikuntatieteellinen tiedekunta Faculty of Sport and Health Sciences Liikuntabiologian laitos Department of Biology of Physical Activity University of Jyväskylä Jyväskylän yliopisto
author_sort Poikonen, Aino
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description Introduction. Doxorubicin (DOX) is widely used as a chemotherapy drug for cancer. However, it is known to affect negatively skeletal muscle mass and function, which can expose to other diseases and decrease survival rate. Presently, there are no accepted drugs for muscle wasting, but myostatin and activin blockers are possible agents. The aim of this study was to investigate the effects of DOX administration alone or combined with blocking of activin receptor signaling on skeletal muscle size, oxidative capacity, mitochondrial function and running performance. Methods. Two identical four-week experiments were conducted in this study. The mice (n = 19 and n = 29 in experiments 1 and 2, respectively) were randomly organized into three groups: 1) controls (Ctrl, n = 6; n = 9), 2) DOX treated group (Dox, n = 6; n = 10) and 3) DOX treated group administered with sACVR2B-Fc (Dox + sACVR2B, n = 7; n = 10). Body composition was determined with DXA imaging and incremental running test was used to examine running capacity. Oxidative capacity was investigated with static biomarkers and mitochondrial function was examined with high resolution respirometry (OROBOROS). Static biomarkers were analyzed with Western immunoblot protein analysis and enzyme assay. PGC-1α gene expression was examined with RT-qPCR method. Results. Skeletal muscle mass decreased significantly in Dox group (p < 0.01), but increased following sACVR2B-Fc administration together with DOX (p < 0.001). Running distance decreased in Dox group compared to Ctrl group (p < 0.01), but did not alter in Dox + sACVR2B group vs. Dox. DOX did not have effect either on oxidative capacity or mitochondrial function. Some static biomarkers changed following sACVR2B-Fc administration. Of those, citrate synthase activity (Krebs cycle enzyme) and porin/VDAC1 protein content increased significantly (p < 0.01) compared to Dox group. The opposite trend was observed in the protein content of respiratory chain subunit (OXPHOS) complexes I (p < 0.001) and V (p < 0.05). However, neither mitochondrial function, other static biomarkers (cytochrome c and total OXPHOS protein contents) nor PGC-1α protein content and isoforms gene expression altered significantly. Conclusion. This study was the first to show decreased maximal running capacity after chemotherapy. This occurred, however without skeletal muscle mitochondrial alterations. sACVR2B-Fc may be a promising strategy to treat chemotherapy induced skeletal muscle loss, without further compromises in running capacity or major mitochondrial alterations.
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Doxorubicin (DOX) is widely used as a chemotherapy drug for cancer. However, it is known to affect negatively skeletal muscle mass and function, which can expose to other diseases and decrease survival rate. Presently, there are no accepted drugs for muscle wasting, but myostatin and activin blockers are possible agents. The aim of this study was to investigate the effects of DOX administration alone or combined with blocking of activin receptor signaling on skeletal muscle size, oxidative capacity, mitochondrial function and running performance.\r\nMethods. Two identical four-week experiments were conducted in this study. The mice (n = 19 and n = 29 in experiments 1 and 2, respectively) were randomly organized into three groups: 1) controls (Ctrl, n = 6; n = 9), 2) DOX treated group (Dox, n = 6; n = 10) and 3) DOX treated group administered with sACVR2B-Fc (Dox + sACVR2B, n = 7; n = 10). Body composition was determined with DXA imaging and incremental running test was used to examine running capacity. Oxidative capacity was investigated with static biomarkers and mitochondrial function was examined with high resolution respirometry (OROBOROS). Static biomarkers were analyzed with Western immunoblot protein analysis and enzyme assay. PGC-1\u03b1 gene expression was examined with RT-qPCR method.\r\nResults. Skeletal muscle mass decreased significantly in Dox group (p < 0.01), but increased following sACVR2B-Fc administration together with DOX (p < 0.001). Running distance decreased in Dox group compared to Ctrl group (p < 0.01), but did not alter in Dox + sACVR2B group vs. Dox. DOX did not have effect either on oxidative capacity or mitochondrial function. Some static biomarkers changed following sACVR2B-Fc administration. Of those, citrate synthase activity (Krebs cycle enzyme) and porin/VDAC1 protein content increased significantly (p < 0.01) compared to Dox group. The opposite trend was observed in the protein content of respiratory chain subunit (OXPHOS) complexes I (p < 0.001) and V (p < 0.05). However, neither mitochondrial function, other static biomarkers (cytochrome c and total OXPHOS protein contents) nor PGC-1\u03b1 protein content and isoforms gene expression altered significantly.\r\nConclusion. This study was the first to show decreased maximal running capacity after chemotherapy. This occurred, however without skeletal muscle mitochondrial alterations. sACVR2B-Fc may be a promising strategy to treat chemotherapy induced skeletal muscle loss, without further compromises in running capacity or major mitochondrial alterations.", "language": "en", "element": "description", "qualifier": "abstract", "schema": "dc"}, {"key": "dc.description.provenance", "value": "Submitted using Plone Publishing form by Aino Poikonen (airojopo) on 2016-06-22 13:59:47.249997. 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spellingShingle Poikonen, Aino Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function doxorubicin luurankolihakset Liikuntafysiologia Exercise Physiology 5011 aerobinen suorituskyky syöpätaudit mitokondriot lihakset syöpähoidot
title Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function
title_full Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function
title_fullStr Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function
title_full_unstemmed Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function
title_short Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function
title_sort effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size oxidative capacity and function
title_txtP Effects of chemotherapy and blocking activin receptor signaling on skeletal muscle size, oxidative capacity and function
topic doxorubicin luurankolihakset Liikuntafysiologia Exercise Physiology 5011 aerobinen suorituskyky syöpätaudit mitokondriot lihakset syöpähoidot
topic_facet 5011 Exercise Physiology Liikuntafysiologia aerobinen suorituskyky doxorubicin lihakset luurankolihakset mitokondriot syöpähoidot syöpätaudit
url https://jyx.jyu.fi/handle/123456789/50573 http://www.urn.fi/URN:NBN:fi:jyu-201606223330
work_keys_str_mv AT poikonenaino effectsofchemotherapyandblockingactivinreceptorsignalingonskeletalmusclesizeoxidati