Abstract
The functional state of denervated muscle is a critical factor in the ability to restore movement after injury- or disease-related paralysis. Here we used peripheral optogenetic stimulation and transcriptome profiling in the mouse whisker system to investigate the time course of changes in neuromuscular function following complete unilateral facial nerve transection. While most skeletal muscles rapidly lose functionality after lower motor neuron denervation, optogenetic muscle stimulation of the paralyzed whisker pad revealed sustained increases in the sensitivity, velocity, and amplitude of whisker movements, and reduced fatigability, starting 48 h after denervation. RNA-seq analysis showed distinct regulation of multiple gene families in denervated whisker pad muscles compared with the atrophy-prone soleus, including prominent changes in ion channels and contractile fibers. Together, our results define the unique functional and transcriptomic landscape of denervated facial muscles and have general implications for restoring movement after neuromuscular injury or disease.NEW & NOTEWORTHY Optogenetic activation of muscle can be used to noninvasively induce movements and probe muscle function. We used this technique in mice to investigate changes in whisker movements following facial nerve transection. We found unexpectedly enhanced functional properties of whisker pad muscle following denervation, accompanied by unique transcriptomic changes. Our findings highlight the utility of the mouse whisker pad for investigating the restoration of movement after paralysis.
Highlights
The functional state of denervated muscle is critical for the restoration of movement after paralysis caused by chronic injury or disease
We used longitudinal optogenetic methods to investigate the time course of whisker movements evoked by nerve or muscle stimulation up to 10 days after facial nerve transection, and in parallel, generated RNA-seq data sets on 1, 3, and 7 days
Responses to brief (5 ms) or prolonged (1,000 ms) 8 mW illumination were similar in both amplitude and velocity, suggesting that the facial nerve responds to optogenetic stimuli in an all-or-none fashion to suprathreshold stimuli
Summary
The functional state of denervated muscle is critical for the restoration of movement after paralysis caused by chronic injury or disease. Functional changes in muscle are well known after lower motor neuron denervation for many types of muscle (Thesleff 1974; Wu et al 2014), with loss of function, atrophy, and reduced capacity for movement being the most common. Gain-offunction changes do not counteract the atrophy and loss of function in most muscles, which presents major problems for generation of contractile force and the ability of muscle to respond to restorative interventions. Available clinical strategies to stimulate neuromuscular function generally target a partially intact nerve instead of direct stimulation of the muscle because it is difficult to produce well-controlled, graded movements using electrical stimulation of muscle (Doucet et al 2012; Griffin and Kim 2011; Ho et al 2014; Peckham and Knutson 2005). Noninvasive, direct stimulation of paralyzed muscle that produces naturalistic movements is highly desirable but has not been achieved using traditional methods
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