Muscle Mitochondria in Vascular Disease: A Novel Genetic Target for Limb Salvage
Goldberg, Emma Joy
This item will be available on: 2024-05-01
Peripheral arterial occlusive disease (PAD) is a manifestation of systemic atherosclerosis defined by an occlusion in the peripheral arteries, most commonly those supplying blood to the lower extremities. Chronic limb threatening ischemia (CLTI) is the most severe clinical manifestation of PAD, and is associated with high rates of limb loss, mortality, and reduced quality of life. Despite increasing PAD prevalence, treatments have been largely stalled over the past two decades, and therapeutics aimed at restoring residual blood flow have been largely unsuccessful in improving limb outcomes, especially for patients with CLTI, suggesting that the restoration of blood flow may not be enough to restore muscle functional ability. Exercise rehabilitation has established efficacy in lessening functional impairments observed in PAD patients who can tolerate it, making it only accessible to patients with less severe PAD manifestations. These findings indicate that targeting and improving ischemic skeletal muscle quality could provide great benefits to patients with PAD. Further supporting this idea, ex vivo studies of skeletal muscle myofibers from patients with PAD demonstrate decreased oxygen consumption and enzyme activity indicative of a unique and intrinsic skeletal muscle bioenergetic dysfunction. The overall aim of this dissertation was to establish whether the restoration of blood flow necessarily guarantees recovery of muscle contractile function, and to determine the role of a specific mitochondrial protein, Cox6a2, in skeletal muscle bioenergetic function. This dissertation ties together multiple in vivo studies using preclinical animal models of PAD, as well as a novel, inducible mouse model of skeletal muscle Cox6a2 loss (Cox6a2 KO). The overarching hypothesis is that the myopathy observed in preclinical models of PAD and in the clinical PAD population is due to dysfunctional skeletal muscle mitochondrial bioenergetics, not perfusion recovery. Further, we hypothesize that skeletal muscle Cox6a2 is required for normal skeletal muscle mitochondrial function, and that its loss will result in a preclinical phenotype that mimics the bioenergetic phenotype observed in the clinical population. Our results establish that the restoration of tissue perfusion does not guarantee the recovery of muscle contractile function or structure in a preclinical model of PAD, and that the loss of Cox6a2 in mature skeletal muscle results in a mitochondrial bioenergetic phenotype.
Goldberg, Emma Joy. (April 2022). Muscle Mitochondria in Vascular Disease: A Novel Genetic Target for Limb Salvage (Doctoral Dissertation, East Carolina University). Retrieved from the Scholarship. (http://hdl.handle.net/10342/10686.)
Goldberg, Emma Joy. Muscle Mitochondria in Vascular Disease: A Novel Genetic Target for Limb Salvage. Doctoral Dissertation. East Carolina University, April 2022. The Scholarship. http://hdl.handle.net/10342/10686. December 08, 2023.
Goldberg, Emma Joy, “Muscle Mitochondria in Vascular Disease: A Novel Genetic Target for Limb Salvage” (Doctoral Dissertation., East Carolina University, April 2022).
Goldberg, Emma Joy. Muscle Mitochondria in Vascular Disease: A Novel Genetic Target for Limb Salvage [Doctoral Dissertation]. Greenville, NC: East Carolina University; April 2022.
East Carolina University