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Pathophysiology of Myotonia and Periodic Paralysis

Award Number: R01AR078198
ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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Pathophysiology of Myotonia and Periodic Paralysis - Project Summary / Abstract Periodic paralysis and myotonia are ion channelopathies of skeletal muscle with debilitating episodes of severe weakness lasting hours to days and activity-dependent muscle stiffness. The long-term goal of this project is to advance our understanding of disease mechanism in these disorders of muscle excitability and to apply this knowledge in the design and pre-clinical testing of therapeutic interventions. Much progress has been made in establishing a causal relationship between the biophysical defect of a mutant channel and the clinical phenotype. For example, over 80 missense mutations have been identified in the NaV1.4 sodium channel, and we have shown by functional expression studies, coupled with simulations of fiber excitability, that mutations with gain of function changes (e.g. impaired inactivation) cause hyperkalemic periodic paralysis (HyperPP) with myotonia. Alternatively, the NaV1.4 mutations in hypokalemic periodic paralysis (HypoPP) are all R/X substitutions in S4 segments of voltage sensor domains that share a common functional defect - the anomalous gating pore leakage current. In all forms of periodic paralysis, the transient attacks of weakness result from sustained depolarization of 𝑉𝑟𝑒௦௧ and loss of excitability, which are often triggered by stress, diet (carbohydrate, salt content, fasting), cold temperature, or exercise. The mechanisms by which these triggers destabilize 𝑉𝑟𝑒௦௧, in the setting of a static defect for a mutant channel, are fundamental open questions in the field and also represent opportunities for therapeutic intervention. A major impediment to progress has been the scarce availability of affected muscle. We created three knock-in mutant mouse models of PP that have robust phenotypes for HyperPP (NaV1.4-M1592V) or HypoPP (NaV1.4-R669H; CaV1.1-R528H). These mouse models have led to new insights on disease mechanism (e.g. recovery from acidosis is a potent trigger of HypoPP) and have led to novel therapeutic interventions that are now in clinical trials (bumetanide inhibition of the NKCC1 cotransporter prevents HypoPP). We will extend our investigations of periodic paralysis by focusing on the impact of ion gradients. Changes in extracellular [K+]o are established triggers for HypoPP (low) or HyperPP (high), but relatively little is known about Na+ and Cl- shifts in PP. Limited human data suggest an acute rise of [Na+]in during an episode of HyperPP or chronically high [Na+]in for HypoPP. In addition, we showed that reducing Cl- influx completely prevents HypoPP attacks. We have developed improved ion-selective microelectrodes, that in combination with the unique resource of our knock-in mutant mice, will enable us to (1) characterize muscle fiber Na+ and Cl- content at rest and during an attack of PP, (2) define the contribution of specific ion transport systems (mutant NaV1.4, NKCC1, Na/K-ATPase, Cl- exchangers) in setting ion concentrations in muscle channelopathies, (3) define the functional consequences of ion gradient perturbations in PP, based on computational modeling and simulation, and (4) use these insights in the design and pre-clinical testing of disease-modifying interventions. .


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $491,495 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	5	7/1/2025	NON-COMPETING CONTINUATION	$491,495
														Subtotal = $491,495

Issue Date FY: 2024 ( Subtotal = $529,723 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	4	6/27/2024	NON-COMPETING CONTINUATION	$529,723
														Subtotal = $529,723

Issue Date FY: 2023 ( Subtotal = $546,106 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	3	6/9/2023	NON-COMPETING CONTINUATION	$546,106
														Subtotal = $546,106

Issue Date FY: 2022 ( Subtotal = $540,644 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	2	6/9/2022	NON-COMPETING CONTINUATION	$540,644
														Subtotal = $540,644

Issue Date FY: 2021 ( Subtotal = $559,887 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Arthritis, Musculoskeletal and Skin Diseases Research	000	1	7/1/2021	NEW	$559,887
														Subtotal = $559,887

Grand Total All Awards = $2,667,855

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Pathophysiology of Myotonia and Periodic Paralysis

Award Number: R01AR078198

ORGANIZATION: NATIONAL INSTITUTE OF ARTHRITIS & MUSCULOSKELETAL & SKIN DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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