NIH abstract: Myotonia congenita (MC) and hyperkalemic periodic paralysis (HPP) are inherited skeletal muscle ion channel diseases. Despite initial descriptions of both diseases many years ago, effective and well tolerated therapy for both disorders has remained elusive. The reason for this is that a detailed understanding of mechanisms regulating muscle excitability in health and disease is lacking. A better understanding of mechanisms underlying muscle dysfunction in the non-dystrophic ion channelopathies is necessary to develop improved therapy for patients. While it is known that muscle in myotonia congenita is hyperexcitable due to reduction of ClC-1 current, the mechanisms underlying two motor symptoms suffered by patients remain poorly understood. The first is transient weakness in recessive forms of myotonia congenita (Becker disease). While the weakness lessens with continued exercise, it is likely a significant contributor to motor dysfunction. Weakness appears to be due to loss of muscle excitability, but the mechanism is unknown. The second symptom is stretch-induced (percussion) myotonia. As muscles must alternately contract and stretch during movement, stretch-induced myotonia may contribute significantly to stiffness. Currently, nothing is known about the mechanism triggering stretch-induced myotonia. We have discovered novel currents that underlie both weakness and stretch-induced myotonia.
In Aims 1 and 2 our goal is characterize these currents and to test the efficacy of available blockers to develop novel therapy for motor dysfunction in myotonia congenita.
In Aim 3 we extend this work to study of motor dysfunction in hyperkalemic periodic paralysis.

Public Health Relevance

Our work is identifying novel electrical currents responsible for the muscle dysfunction in diseases of electrical signaling. If successful, our studies will result in the development of novel therapies for patients with a number different skeletal muscle diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR074985-02
Application #
9895630
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Cheever, Thomas
Project Start
2019-04-01
Project End
2024-03-31
Budget Start
2020-04-01
Budget End
2021-03-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
Wright State University
Department
Type
DUNS #
047814256
City
Dayton
State
OH
Country
United States
Zip Code
45435