Abstract
Skeletal muscle dysfunction in chronic obstructive pulmonary disease (COPD) patients is common. Neuromuscular Electrical Stimulation (NMES) is a powerful exercise training that may relieve muscle dysfunction in COPD. This study investigated whether electrical stimulation may have atypical adaptations via activation of miRNA related pathways in counteracting COPD muscle dysfunction. Forty-eight male Sprague-Dawley rats were randomly assigned to 3 groups. With the exception of the rats in the control group, the experimental rats were exposed to chronic intermittent hypoxia-hypercapnia (CIHH) (9∼11%O2,5.5∼6.5%CO2) for 2 or 4 weeks. Electrical stimulation was performed immediately after each CIHH session. Following assessment of the running capacity, biopsy samples were obtained from the gastrocnemius of the rats. The miR-1, miR-133a and miR-133b levels were measured, as well as their related proteins: phosphorylation of Akt (p-AKT), PGC-1alpha (PGC-1α), histone deacetylase 4 (HDAC4) and serum response factor (SRF). Myosin heavy chainⅡa (MHCⅡa) and myosin heavy chainⅡb (MHCⅡb) were also measured to assess fiber type changes. After 2 weeks, compared with the controls, only miR-1 and miR-133a were significantly increased (p<0.05) in the exposure group. After 4 weeks, the exposure group exhibited a decreased running distance (p = 0.054) and MHCⅡa-to-MHCⅡb shift (p<0.05). PGC-1α (p = 0.051), nuclear HDAC4 (p = 0.058), HDAC4, p-AKT, PGC-1α and SRF was also significantly decreased (p<0.05). In contrast, miR-1 and miR-133a were significantly increased (p<0.05). Four weeks of electrical stimulation can partly reversed those changes, and miR-133b exhibited a transient increase after 2 weeks electrical stimulation. Our study indicate miRNAs may have roles in the response of CIHH-impaired muscle to changes during electrical stimulation.
Highlights
Chronic obstructive pulmonary disease (COPD) is a worldwide disease
We regarded Myosin heavy chainIIa (MHCIIa) as the slow MHC and myosin heavy chainIIb (MHCIIb) as the fast MHC because in rat muscles, the abundance of mitochondria and oxidative enzymes are highest in IIa fibers and lowest in IIb fibers, which are very different from human muscles[22, 23]
Four weeks (Fig 1B) of Chronic intermittent hypoxia hypercapnia (CIHH) exposure resulted in a significant decrease in MHCIIa in the hypoxia-hypercapnia group (HH) group compared with the normal control group (NC) group (p
Summary
Skeletal muscle dysfunction is common in COPD patients[1, 2]. Several studies have demonstrated that skeletal muscle dysfunction is associated with low exercise tolerance and a reduction in quality of life and may predict poor prognosis[3,4,5]. The major reason for muscle dysfunction may be I-to-II muscle fiber type shift and muscle atrophy, which lead to weakness and reduced endurance capacity in patients with COPD [6, 7]. Chronic intermittent hypoxia hypercapnia (CIHH) is an animal model with demonstrated contributions to the understanding of the development of COPD pathophysiology[8,9,10]. Exposure to CIHH deteriorated the muscles of the experimental rats when the exposure time was prolonged more than 2 weeks[9]
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