Contractile abnormalities of mouse muscles expressing hyperkalemic periodic paralysis mutant NaV1.4 channels do not correlate with Na+ influx or channel content.
Hyperkalemic periodic paralysis (HyperKPP) is characterized by myotonic discharges that occur between episodic attacks of paralysis. Individuals with HyperKPP rarely suffer respiratory distress even though diaphragm muscle expresses the same defective Na(+) channel isoform (NaV1.4) that causes symptoms in limb muscles. We tested the hypothesis that the extent of the HyperKPP phenotype (low force generation and shift toward oxidative type I and IIA fibers) in muscle is a function of 1) the NaV1.4 channel content and 2) the Na(+) influx through the defective channels [i.e., the tetrodotoxin (TTX)-sensitive Na(+) influx]. We measured NaV1.4 channel protein content, TTX-sensitive Na(+) influx, force generation, and myosin isoform expression in four muscles from knock-in mice expressing a NaV1.4 isoform corresponding to the human M1592V mutant. The HyperKPP flexor digitorum brevis muscle showed no contractile abnormalities, which correlated well with its low NaV1.4 protein content and by far the lowest TTX-sensitive Na(+) influx. In contrast, diaphragm muscle expressing the HyperKPP mutant contained high levels of NaV1.4 protein and exhibited a TTX-sensitive Na(+) influx that was 22% higher compared with affected extensor digitorum longus (EDL) and soleus muscles. Surprisingly, despite this high burden of Na(+) influx, the contractility phenotype was very mild in mutant diaphragm compared with the robust abnormalities observed in EDL and soleus. This study provides evidence that HyperKPP phenotype does not depend solely on the NaV1.4 content or Na(+) influx and that the diaphragm does not depend solely on Na(+)-K(+) pumps to ameliorate the phenotype.
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; and.
Brooke
B
Lucas
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; and.
Tarek
T
Ammar
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; and.
Shiemaa
S
Khogali
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; and.
Danica
D
DeJong
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; and.
Michael
M
Barbalinardo
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; and.
Cameron
C
Nishi
Department of Neurology, University of Massachusetts Medical School, Worcester, Massachusetts.
Lawrence J
LJ
Hayward
Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; and jmrenaud@uottawa.ca.
Jean-Marc
JM
Renaud
D000818:Animals; D006801:Humans; D051379:Mice; D009119:Muscle Contraction / Q000235:genetics*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D062553:NAV1.4 Voltage-Gated Sodium Channel / Q000235:genetics* / Q000378:metabolism; D020513:Paralysis, Hyperkalemic Periodic / Q000235:genetics* / Q000378:metabolism; D011188:Potassium / Q000378:metabolism; D012964:Sodium / Q000378:metabolism*
D062553:NAV1.4 Voltage-Gated Sodium Channel; C491391:Scn4a protein, mouse; D012964:Sodium; D009218:Myosins; D011188:Potassium
Ca2+ entry; Cav1.1; Na+ influx; Na+-K+-ATPase pump; SOCE; fiber type; ouabain; tetrodotoxin