Hyperkalemic periodic paralysis (HyperKPP) is characterized by myotonic discharges and weakness/paralysis. It is a channelopathy that is caused by mutation in the SCN4A gene that encodes for the skeletal muscle Na+ channel isoform (Nav1.4) α-subunit. Limb muscles are severely affected while breathing musculature is rarely affected even though diaphragm expresses the Nav1.4 channel. The objective of this study was to investigate the mechanism(s) that render the HyperKPP diaphragm asymptomatic in order to find a novel long lasting therapeutic approach, to treat HyperKPP symptoms. A HyperKPP mouse model carrying the M1592V mutation was used because it has a similar phenotype to that of patients carrying the same mutation. HyperKPP diaphragm, the limb muscles soleus and EDL all had a higher tetrodotoxin (TTX) sensitive Na+ influx than wild type (WT), but only the soleus and EDL had a depolarized resting potential, lower force and greater K+-induced force loss when compared to WT. The lack of a membrane depolarization in HyperKPP diaphragm was because of greater electrogenic contribution of the Na+ K+ ATPase pump compared to WT while such increase was not observed in EDL and soleus. HyperKPP diaphragm also had greater action potential amplitude than EDL and soleus possibly because of higher Na+ K+ ATPase pump maintaining a low [Na+]i. An inhibition of PKA, but not of PKC, increased the sensitivity of the HyperKPP diaphragm to the K+-induced force depression. So, HyperKPP soleus was exposed to forskolin to increase cAMP levels in order to activate PKA to document whether greater activity of PKA will alleviate HyperKPP symptoms. At 4.7 mM K+, forskolin increased force production, but worsened the decrease in force at 8 and 11 mM K+. Forskolin also did not improve membrane excitability. Pinacidil a KATP channel opener, improved force production at all [K+]e by causing a hyperpolarization of resting EM which then allowed for greater action potential amplitude and more excitable fibers. It is concluded that the development of a better therapeutic approach to treat HyperKPP can include a mechanism which activates Na+ K+ ATPase pumps and KATP channels.
| Identifer | oai:union.ndltd.org:uottawa.ca/oai:ruor.uottawa.ca:10393/35745 |
| Date | January 2017 |
| Creators | Ammar, Tarek |
| Contributors | Renaud, Jean-Marc |
| Publisher | Université d'Ottawa / University of Ottawa |
| Source Sets | Université d’Ottawa |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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