Preclinical and Clinical Projects

Developing in vivo measures of motor unit connectivity and muscle contractility for assessment of animal models 

Over the last few years, the lab has developed and refined in vivo assays of neuromuscular function.  We have refined techniques for assessing motor unit connectivity including compound muscle action potential and motor unit number estimates in neonatal to elderly mice.  We have investigated these measures and their responsiveness to genetic manipulation and therapeutic testing in spinal muscular atrophy, hereditary neuropathy, autoimmune neuropathyhereditary spastic paraparesis, and aging. We have also investigated electrical impedance myography in hereditary myopathies, spinal muscular atrophy, and aging in collaboration with the Rutkove lab.

 

Motor neuron degeneration and repair in age-related loss of physical function and peripheral nerve injury

Muscle function is modulated by the central nervous system (CNS) via the number and the firing rates of motor units during a muscular contraction. The motor unit, comprised of a motor neuron and all of the muscle fibers it innervates, is the smallest functional unit of the neuromuscular system.  As a non-dividing and non-replaceable cell population, we are interested in understanding the role of motor neuron degeneration in loss of physical function in older adults. We recently showed that loss of muscle size and function are closely related to motor unit number in aged mice.  We are currently exploring degenerative and compensatory mechanisms of motor unit loss and repair as well as potential therapeutics to reduce the burden of sarcopenia and peripheral nerve injury on society.

 

Effects of muscle alterations on motor unit maintenance and degeneration

We are investigating the effects of increasing muscle size (hypertrophy) on the functional status of motor units during aging.  As part of this project, we are leveraging the power of adeno-associated viral  vectors to deliver follistatin in order to induce muscle hypertrophy in aged mice.

 

Investigating ranolazine as a therapeutic for dystrophic and nondystrophic forms of myotonia 

We recently completed three open-label trials in myotonia congenita, paramyotonia congenita, and myotonic dystrophy type 1.  We currently planning for a future multi-center, placebo controlled trial.

 

Investigating central nervous system disease burden and the role of motor neuron dysfunction in motor impairment in patients with myotonic dystrophy type 1 (DM1) 

Fatigue is a major symptom in patients with myotonic dystrophy.  As part of our recently completed clinical trials of ranolazine as a therapeutic treatment of muscle hyperexcitability (myotonia) we identified a potential role of disrupted motor unit control in fatigue in patients with myotonic dystrophy type 1. We are currently exploring these findings in a single center clinical investigation.