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Acute Mechanisms of Skeletal Muscle Decline and Rehabilitative Recovery Following Ischemic Stroke

Balch, Maria Helen Harley
http://orcid.org/0000-0003-2011-6345
http://rave.ohiolink.edu/etdc/view?acc_num=osu159558748119711

Abstract Details

2020, Doctor of Philosophy, Ohio State University, Anatomy.
With a prevalence surpassing 80 million, stroke is a prominent cause of patient mortality and disability world-wide. The majority of strokes are ischemic in etiology, caused by cerebrovascular occlusion that deprives the brain of oxygen and glucose. The consequential continuous activation of excitatory neurotransmitter receptors, intracellular calcium accumulation, inflammation, and reactive oxygen species proliferation ultimately result in neuronal death. Beyond the ischemic brain insult, a growing body of evidence points to far-reaching pathophysiological consequences of acute ischemic stroke. Shortly after stroke onset, impairments to immune, autonomic, and motor pathways lead to dysfunction across organ systems. These end organ abnormalities play a major role in the morbidity and mortality of acute ischemic stroke and argue for the classification of stroke as a systemic disease. As the leading global contributor to disability, stroke necessitates rehabilitation to facilitate functional recovery. Yet despite the need for evidence-based therapies, little attention has been given to the neuromuscular response following ischemic stroke. Motor units are comprised of a single lower motor neuron axon and all myofibers it innervates. Though not directly injured by the central stroke lesion, lower motor neurons rely on cortical input for motor communication at the neuromuscular junction. To that end, we aimed to (a) characterize the impact of ischemic stroke on the neuromuscular system and (b) explore potential therapeutic modulation of stroke-induced alterations at the neuromuscular interface. Through in vivo longitudinal study, we investigated muscle contractility and identified a reduction in plantarflexion tetanic torque of the stroke-affected hindlimb. We also tested motor unit functionality and discovered that stroke significantly reduced motor unit number estimation. Rather than an actual loss of motor units from denervation, our subsequent investigation of neuromuscular junction morphology suggested reduction in motor unit number estimation was an artifact of maladaptive stroke-induced polyneuronal innervation. We also observed post-stroke expansion of pre- and postsynaptic structures at the neuromuscular interface, resulting in larger neuromuscular junctions with diminished receptor clustering. Given our previous report that mechanical massage (Robot-Assisted Mechanical Therapy (RAMT)) improved functional outcomes and protected against myokine disturbance after stroke, we examined the impact of RAMT on neuromuscular junction integrity. RAMT treatment significantly reduced frequency of polyneuronal innervation and attenuated the neuromuscular junction expansion observed after stroke. RAMT had no effect on the stroke-related decrease in junction complexity. Additional experiments were outlined in pursuit of molecular explanation for the therapeutic effects of RAMT. One such route of investigation focused on RAMT’s modulation of inflammatory myokines in stroke-affected muscle. We explored mechano-sensitive microRNAs and identified microRNA-22 as a potential candidate for future study. Given our preliminary data, we propose that the immune cell profile of stroke-affected skeletal muscle is modulated by RAMT and that expression of microRNA-22 may promote a reparative shift in macrophage phenotype. This work addresses the systemic effects of ischemic stroke across organ systems and, given the impact of stroke-induced disability, focuses investigation on the neuromuscular interface. We describe the consequences of ischemic stroke on motor unit function and neuromuscular junction morphology while presenting therapeutic benefit in mechanical massage. Ongoing work will further define neuromuscular changes after stroke, determine responsible signaling mechanisms, and provide evidence-based methods to therapeutically improve functional outcomes.
Eileen Kalmar, PhD (Advisor)
Shahid Nimjee, MD, PhD (Advisor)
W. David Arnold, MD (Committee Member)
Cameron Rink, PhD (Committee Member)
189 p.
Anatomy and Physiology; Medicine; Neurobiology; Neurology; Neurosciences; Pathology; Physical Therapy; Physiology; Rehabilitation; Therapy
acute ischemic stroke; functional disability; neuromuscular system; skeletal muscle; neuromuscular junction; motor unit electrophysiology; stroke rehabilitation; mechanical therapy; massage; therapeutic recovery; pathophysiology

Recommended Citations

Citations

  • Balch, M. H. H. (2020). Acute Mechanisms of Skeletal Muscle Decline and Rehabilitative Recovery Following Ischemic Stroke [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu159558748119711

    APA Style (7th edition)

  • Balch, Maria. Acute Mechanisms of Skeletal Muscle Decline and Rehabilitative Recovery Following Ischemic Stroke. 2020. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu159558748119711.

    MLA Style (8th edition)

  • Balch, Maria. "Acute Mechanisms of Skeletal Muscle Decline and Rehabilitative Recovery Following Ischemic Stroke." Doctoral dissertation, Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu159558748119711

    Chicago Manual of Style (17th edition)

osu159558748119711
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This open access ETD is published by The Ohio State University and OhioLINK.