Several conditions such as diseases or accidental and chirurgical trauma can lead to the loss of nerve control of skeletal muscles. Optogenetic control of excitability, which has revolutionized neurobiological research but has never been attempted in adult skeletal muscles, is a promising alternative for the recovery of muscle function. However, several basic questions need to be answered prior to the practical implementation of optogenetic approaches in vivo.
In Aim 1 of this proposal we will investigate whether activating (e.g. channelrhodopsin 2) and silencing actuators (e.g. archeorhodopsin 3) are expressed in sufficient quantities in adult skeletal muscle fibers so that pulses of illuminatin can either elicit action potentials (APs), or inhibit electrically elicited APs, respectively. This information will allow us to comparatively test (in Aim 2) the ability of light and electrical stimulation to attain fine control of the mechanical activity of intact muscles expressing optical actuators. We will use two approaches for the specific transfection of muscle with plasmids encoding for opsins: electroporation and adeno-associated virus. This will enable us to investigate the feasibility of using novel approaches using wireless optoelectronic implantable devices for the fine control of muscles in the intact animal. The outcome of the innovative research approaches proposed in this grant are expected to pave the way for the practical use of optogenetics tools to restore the control of muscle output when they are deemed inactive due to the absence of nerve inputs.

Public Health Relevance

The main goal of this proposal is to enable the use of optogenetic actuators that can be activated by light as a substitute for the electrical control of skeletal muscle function. The optogenetic methodology resulting from these studies may prove to be translatable into therapeutic approaches to restore muscle function in individuals affected by diseases or traumas leading to the loss of muscle innervation. Thus, the proposed research is highly transformative and imminently relevant to the NIH's mission to improve public health since its outcomes will likely translate in definite improvements in quality of life.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Exploratory/Developmental Grants (R21)
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Skeletal Muscle and Exercise Physiology Study Section (SMEP)
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Boyce, Amanda T
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University of California Los Angeles
Schools of Medicine
Los Angeles
United States
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Peter, Angela K; Miller, Gaynor; Capote, Joana et al. (2017) Nanospan, an alternatively spliced isoform of sarcospan, localizes to the sarcoplasmic reticulum in skeletal muscle and is absent in limb girdle muscular dystrophy 2F. Skelet Muscle 7:11
DiFranco, Marino; Kramerova, Irina; Vergara, Julio L et al. (2016) Attenuated Ca(2+) release in a mouse model of limb girdle muscular dystrophy 2A. Skelet Muscle 6:11