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Published on: November 3, 2013
Myosin loss in denervated rat soleus muscle after dexamethasone treatment
Hideo Horinouchi1, Toshihide Kumamoto, Noriyuki Kimura
1Division of Neurology and Neuromuscular Disorders, Department of Brain and Nerve Science, Oita University Faculty of Medicine, Oita, Japan. horinouc@oita-med.ac.jp
Insights
Critical illness myopathy involves myosin loss, potentially due to altered myosin transcription and increased ubiquitin ligases. This study investigates the mechanisms behind myosin filament loss in critical illness myopathy.
Area of Science:
- Muscle physiology
- Cellular biology
- Pathology
Background:
- Critical illness myopathy (CIM) is characterized by acute muscle wasting.
- A key pathological feature of CIM is the selective loss of thick myosin filaments.
- CIM is associated with critical illness and exposure to corticosteroids and neuromuscular blocking agents.
Purpose of the Study:
- To investigate the pathomechanism of myosin loss in critical illness myopathy.
- To clarify the expression of myosin heavy chain (MHC) and ubiquitin ligase atrogin-1 in CIM.
- To understand the role of the ubiquitin-proteasome pathway in CIM-related muscle wasting.
Main Methods:
- Histological, immunohistochemical, SDS-PAGE, and RT-PCR analyses were performed on rat soleus muscles.
- Experiments involved saline and dexamethasone treatments on both innervated and denervated muscles.
- Expression levels of MHC and atrogin-1 were assessed.
Main Results:
- Dexamethasone treatment led to significant MHC loss in denervated rat muscles.
- mRNA expression of the ubiquitin ligase atrogin-1 was markedly increased in denervated, dexamethasone-treated muscles.
- mRNA levels of the myosin isoform MHC I were decreased in these muscles, indicating altered transcription.
Conclusions:
- Selective myosin loss in CIM may result from altered myosin transcription rates.
- Upregulation of multiple ubiquitin ligases likely contributes to myosin loss via the ubiquitin-proteasome pathway.
- These findings provide insight into the molecular mechanisms underlying muscle wasting in critical illness.
Objective:
Critical illness myopathy (CIM) is an acute myopathy that appears in the setting of critical illness or during exposure to corticosteroids and neuromuscular blocking agents. Its pathological feature is selective loss of thick myosin filaments. Our aim is to gain further insight into the pathomechanism of myosin loss in this myopathy.
Methods:
To clarify the expression of myosin heavy chain (MHC) and ubiquitin ligase atrogin-1 in this myopathy, histological, immunohistochemical, SDS-PAGE, and semiquantitative reverse transcriptase-polymerase chain reaction studies were performed on innervated and denervated rat soleus muscles after saline and dexamethasone treatments.
Results:
Denervated muscles from dexamethasone-treated rats showed marked MHC loss. The mRNA expression of ubiquitin ligase atrogin-1 was significantly increased in denervated dexamethasone-treated muscles, suggesting that the ubiquitin-proteasome pathway plays an important role in muscular wasting in CIM. Furthermore, mRNA levels of MHC I, a myosin isoform, were decreased in the denervated dexamethasone-treated muscles.
Conclusion:
Our findings suggest that an altered transcription rate of myosin, as well as the upregulation of multiple ubiquitin ligases, may be responsible for selective myosin loss in this myopathy.
