Targeted ablation of the cellular inhibitor of apoptosis 1 (cIAP1) attenuates denervation-induced skeletal muscle atrophy
Abstract Background Skeletal muscle atrophy is a pathological condition that contributes to morbidity in a variety of conditions including denervation, cachexia, and aging. Muscle atrophy is characterized as decreased muscle fiber cross-sectional area and protein content due, in part, to the proteol...
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doaj-c2c177ddccd1405a9f6a8140cf28c2322020-11-25T03:09:20ZengBMCSkeletal Muscle2044-50402019-05-019111310.1186/s13395-019-0201-6Targeted ablation of the cellular inhibitor of apoptosis 1 (cIAP1) attenuates denervation-induced skeletal muscle atrophyNeena Lala-Tabbert0Rim Lejmi-Mrad1Kristen Timusk2Marina Fukano3Janelle Holbrook4Martine St-Jean5Eric C. LaCasse6Robert G. Korneluk7Apoptosis Research Centre, Children’s Hospital of Eastern Ontario Research InstituteApoptosis Research Centre, Children’s Hospital of Eastern Ontario Research InstituteApoptosis Research Centre, Children’s Hospital of Eastern Ontario Research InstituteApoptosis Research Centre, Children’s Hospital of Eastern Ontario Research InstituteApoptosis Research Centre, Children’s Hospital of Eastern Ontario Research InstituteApoptosis Research Centre, Children’s Hospital of Eastern Ontario Research InstituteApoptosis Research Centre, Children’s Hospital of Eastern Ontario Research InstituteApoptosis Research Centre, Children’s Hospital of Eastern Ontario Research InstituteAbstract Background Skeletal muscle atrophy is a pathological condition that contributes to morbidity in a variety of conditions including denervation, cachexia, and aging. Muscle atrophy is characterized as decreased muscle fiber cross-sectional area and protein content due, in part, to the proteolytic activities of two muscle-specific E3 ubiquitin ligases: muscle RING-finger 1 (MuRF1) and muscle atrophy F-box (MAFbx or Atrogin-1). The nuclear factor-kappa B (NF-κB) pathway has emerged as a critical signaling network in skeletal muscle atrophy and has become a prime therapeutic target for the treatment of muscle diseases. Unfortunately, none of the NF-κB targeting drugs are currently being used to treat these diseases, likely because of our limited knowledge and specificity, for muscle biology and disease. The cellular inhibitor of apoptosis 1 (cIAP1) protein is a positive regulator of tumor necrosis factor alpha (TNFα)-mediated classical NF-κB signaling, and cIAP1 loss has been shown to enhance muscle regeneration during acute and chronic injury. Methods Sciatic nerve transection in wild-type, cIAP1-null and Smac mimetic compound (SMC)-treated mice was performed to investigate the role of cIAP1 in denervation-induced atrophy. Genetic in vitro models of C2C12 myoblasts and primary myoblasts were also used to examine the role of classical NF-κB activity in cIAP1-induced myotube atrophy. Results We found that cIAP1 expression was upregulated in denervated muscles compared to non-denervated controls 14 days after denervation. Genetic and pharmacological loss of cIAP1 attenuated denervation-induced muscle atrophy and overexpression of cIAP1 in myotubes was sufficient to induce atrophy. The induction of myotube atrophy by cIAP1 was attenuated when the classical NF-κB signaling pathway was inhibited. Conclusions These results demonstrate the cIAP1 is an important mediator of NF-κB/MuRF1 signaling in skeletal muscle atrophy and is a promising therapeutic target for muscle wasting diseases.http://link.springer.com/article/10.1186/s13395-019-0201-6cIAP1NF-κBMuscle atrophyMuRF1Atrogin-1Denervation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Neena Lala-Tabbert Rim Lejmi-Mrad Kristen Timusk Marina Fukano Janelle Holbrook Martine St-Jean Eric C. LaCasse Robert G. Korneluk |
spellingShingle |
Neena Lala-Tabbert Rim Lejmi-Mrad Kristen Timusk Marina Fukano Janelle Holbrook Martine St-Jean Eric C. LaCasse Robert G. Korneluk Targeted ablation of the cellular inhibitor of apoptosis 1 (cIAP1) attenuates denervation-induced skeletal muscle atrophy Skeletal Muscle cIAP1 NF-κB Muscle atrophy MuRF1 Atrogin-1 Denervation |
author_facet |
Neena Lala-Tabbert Rim Lejmi-Mrad Kristen Timusk Marina Fukano Janelle Holbrook Martine St-Jean Eric C. LaCasse Robert G. Korneluk |
author_sort |
Neena Lala-Tabbert |
title |
Targeted ablation of the cellular inhibitor of apoptosis 1 (cIAP1) attenuates denervation-induced skeletal muscle atrophy |
title_short |
Targeted ablation of the cellular inhibitor of apoptosis 1 (cIAP1) attenuates denervation-induced skeletal muscle atrophy |
title_full |
Targeted ablation of the cellular inhibitor of apoptosis 1 (cIAP1) attenuates denervation-induced skeletal muscle atrophy |
title_fullStr |
Targeted ablation of the cellular inhibitor of apoptosis 1 (cIAP1) attenuates denervation-induced skeletal muscle atrophy |
title_full_unstemmed |
Targeted ablation of the cellular inhibitor of apoptosis 1 (cIAP1) attenuates denervation-induced skeletal muscle atrophy |
title_sort |
targeted ablation of the cellular inhibitor of apoptosis 1 (ciap1) attenuates denervation-induced skeletal muscle atrophy |
publisher |
BMC |
series |
Skeletal Muscle |
issn |
2044-5040 |
publishDate |
2019-05-01 |
description |
Abstract Background Skeletal muscle atrophy is a pathological condition that contributes to morbidity in a variety of conditions including denervation, cachexia, and aging. Muscle atrophy is characterized as decreased muscle fiber cross-sectional area and protein content due, in part, to the proteolytic activities of two muscle-specific E3 ubiquitin ligases: muscle RING-finger 1 (MuRF1) and muscle atrophy F-box (MAFbx or Atrogin-1). The nuclear factor-kappa B (NF-κB) pathway has emerged as a critical signaling network in skeletal muscle atrophy and has become a prime therapeutic target for the treatment of muscle diseases. Unfortunately, none of the NF-κB targeting drugs are currently being used to treat these diseases, likely because of our limited knowledge and specificity, for muscle biology and disease. The cellular inhibitor of apoptosis 1 (cIAP1) protein is a positive regulator of tumor necrosis factor alpha (TNFα)-mediated classical NF-κB signaling, and cIAP1 loss has been shown to enhance muscle regeneration during acute and chronic injury. Methods Sciatic nerve transection in wild-type, cIAP1-null and Smac mimetic compound (SMC)-treated mice was performed to investigate the role of cIAP1 in denervation-induced atrophy. Genetic in vitro models of C2C12 myoblasts and primary myoblasts were also used to examine the role of classical NF-κB activity in cIAP1-induced myotube atrophy. Results We found that cIAP1 expression was upregulated in denervated muscles compared to non-denervated controls 14 days after denervation. Genetic and pharmacological loss of cIAP1 attenuated denervation-induced muscle atrophy and overexpression of cIAP1 in myotubes was sufficient to induce atrophy. The induction of myotube atrophy by cIAP1 was attenuated when the classical NF-κB signaling pathway was inhibited. Conclusions These results demonstrate the cIAP1 is an important mediator of NF-κB/MuRF1 signaling in skeletal muscle atrophy and is a promising therapeutic target for muscle wasting diseases. |
topic |
cIAP1 NF-κB Muscle atrophy MuRF1 Atrogin-1 Denervation |
url |
http://link.springer.com/article/10.1186/s13395-019-0201-6 |
work_keys_str_mv |
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