# Impact of Rad-mediated inhibition of Cav1.1 on muscle composition and contractile function

> **NIH NIH R03** · UNIVERSITY OF MARYLAND BALTIMORE · 2020 · $89,525

## Abstract

Expression of the monomeric G protein Rad (Ras-like Associated with Diabetes) is elevated in skeletal muscle
of Amyotrophic Lateral Sclerosis (ALS) patients and mouse models of neuromuscular disease. The elevated
expression of Rad is likely to impact muscle function because Rad is a constitutively-active inhibitor of the
skeletal muscle L-type Ca2+ channel (CaV1.1), which serves as the voltage-sensor for excitation-contraction
(EC) coupling. It has been established that impaired EC coupling contributes to muscle weakness in multiple
neuromuscular disorders such as ALS. This depression of excitability (termed “EC un-coupling”) is a direct
consequence of a fewer number of functional CaV1.1 channels present in the plasma membrane. In addition,
targeted knock-down of CaV1.1 in vivo causes significant muscle atrophy. Taken together, these observations
suggest that Rad blunts force generation and can initiate morphological changes in skeletal muscle. Indeed,
preliminary data indicate that overexpression of Rad in normal mouse skeletal muscle impairs EC coupling,
causes profound atrophy and changes muscle metabolic profile. Thus, the purpose of this R03 small grant
proposal is to investigate the broader consequences of chronic inhibition of CaV1.1 in skeletal muscle.
Specific Aim 1 will determine whether long-term Rad-induced impairment of EC coupling manifests in reduced
muscle force generation. To do so, otherwise normal gastrocnemius muscle will be infected with an Adeno-Associated Virus (AAV1) encoding a skeletal muscle-targeted Venus fluorescent protein-Rad fusion construct
(tMCK-V-Rad). Two, four, and six months post-infection, the ability of tMCK-V-Rad to reduce absolute and/or
specific muscle force generation in response to nerve and direct muscle stimulation will be evaluated using an
in vivo force assay. Specific Aim 2 will investigate the idea that elevated Rad expression can drive changes in
muscle mass and composition similar to those observed in progressive neurodegenerative disease. In these
experiments, normal mouse hindlimb muscles infected with tMCK-V-Rad will be harvested, frozen, sectioned
and probed with antibodies directed to Type I, Type IIA, Type IIX and Type IIB myosin heavy chains to test the
hypothesis that elevated Rad expression causes a shift in muscle fiber-type profile from more glycolytic fibers
towards more oxidative fibers.

## Key facts

- **NIH application ID:** 9871445
- **Project number:** 1R03AG065626-01
- **Recipient organization:** UNIVERSITY OF MARYLAND BALTIMORE
- **Principal Investigator:** Roger Alan Bannister
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $89,525
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9871445

## Citation

> US National Institutes of Health, RePORTER application 9871445, Impact of Rad-mediated inhibition of Cav1.1 on muscle composition and contractile function (1R03AG065626-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9871445. Licensed CC0.

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