Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita

Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita

Bibliographic Details
Main Author: Hawash, Ahmed Alaa
Language:English
Published: Wright State University / OhioLINK 2017
Subjects:
Biology
Health Sciences
Medicine
Neurobiology
Neurology
Neurosciences
Myotonia
Myotonia Congenita
Muscle
Skeletal Muscle
Electrophysiology
Repetitive Firing
Persistent Currents
Persistent Inward Currents
PIC
PICs
Hyperexcitability
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=wright1500932300888521
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-wright15009323008885212021-08-03T07:03:35Z Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita Hawash, Ahmed Alaa Biology Health Sciences Medicine Neurobiology Neurology Neurosciences Myotonia Myotonia Congenita Muscle Skeletal Muscle Electrophysiology Repetitive Firing Persistent Currents Persistent Inward Currents PIC PICs Hyperexcitability Myotonia congenita is a rare skeletal muscle channelopathy caused by a reduced chloride channel (ClC-1) current, which results in debilitating muscle hyperexcitability, prolonged contractions, and transient episodes of weakness. The excitatory events that trigger myotonic action potentials in the absence of stabilizing ClC-1 current are not fully understood. My in vitro intracellular recordings from a mouse homozygous knockout of ClC-1 revealed a slow after-depolarization (AfD) that triggers myotonic action potentials. The AfD is well-explained by a tetrododoxin-sensitive and voltage-dependent Na+ persistent inward current (NaPIC). Notably, this NaPIC undergoes slow inactivation over seconds, thus providing the first mechanistic explanation for the end of myotonic runs. Highlighting the significance of this mechanism, we show that ranolazine and elevated serum divalent cations eliminate myotonia by inhibiting AfD and NaPIC. The electrophysiological events responsible for the transient weakness are not well understood either. My in vitro intracellular recordings revealed a novel behavior, in which the muscle is functionally inexcitable for seconds to minutes. This hanging behavior, as I refer to it, is likely to be responsible for periods of weakness described by patients and is explained by another persistent inward current. Partial pharmacological block of this other PIC decreases the hanging behavior in myotonic muscle.This work significantly changes our understanding of the mechanisms underlying myotonia and transient weakness seen in myotonia congenita and reveals a novel and highly effective therapeutic target. 2017-07-28 English text Wright State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=wright1500932300888521 http://rave.ohiolink.edu/etdc/view?acc_num=wright1500932300888521 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Biology
Health Sciences
Medicine
Neurobiology
Neurology
Neurosciences
Myotonia
Myotonia Congenita
Muscle
Skeletal Muscle
Electrophysiology
Repetitive Firing
Persistent Currents
Persistent Inward Currents
PIC
PICs
Hyperexcitability
spellingShingle Biology
Health Sciences
Medicine
Neurobiology
Neurology
Neurosciences
Myotonia
Myotonia Congenita
Muscle
Skeletal Muscle
Electrophysiology
Repetitive Firing
Persistent Currents
Persistent Inward Currents
PIC
PICs
Hyperexcitability
Hawash, Ahmed Alaa
Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita
author Hawash, Ahmed Alaa
author_facet Hawash, Ahmed Alaa
author_sort Hawash, Ahmed Alaa
title Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita
title_short Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita
title_full Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita
title_fullStr Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita
title_full_unstemmed Persistent Inward Currents Play a Role in Muscle Dysfunction Seen inMyotonia Congenita
title_sort persistent inward currents play a role in muscle dysfunction seen inmyotonia congenita
publisher Wright State University / OhioLINK
publishDate 2017
url http://rave.ohiolink.edu/etdc/view?acc_num=wright1500932300888521
work_keys_str_mv AT hawashahmedalaa persistentinwardcurrentsplayaroleinmuscledysfunctionseeninmyotoniacongenita
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