title: Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia.
abstract: Critical limb ischemia (CLI) is the most severe clinical presentation of peripheral arterial disease and manifests as chronic limb pain at rest and/or tissue necrosis. Current clinical interventions are largely ineffective and therapeutic angiogenesis based trials have shown little efficacy, highlighting the dire need for new ideas and novel therapeutic approaches. Despite a decade of research related to skeletal muscle as a determinant of morbidity and mortality outcomes in CLI, very little progress has been made toward an effective therapy aimed directly at the muscle myopathies of this disease. Within the muscle cell, mitochondria are well positioned to modulate the ischemic cellular response, as they are the principal sites of cellular energy production and the major regulators of cellular redox charge and cell death. In this mini review, we update the crucial importance of skeletal muscle to CLI pathology and examine the evolving influence of muscle and endothelial cell mitochondria in the complex ischemic microenvironment. Finally, we discuss the novelty of muscle mitochondria as a therapeutic target for ischemic pathology in the context of the complex co-morbidities often associated with CLI.
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University Greenville, NC, USA.
authors.forename: Terence E
authors.initials: TE
authors.lastname: Ryan
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University Greenville, NC, USA.
authors.forename: Cameron A
authors.initials: CA
authors.lastname: Schmidt
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University Greenville, NC, USA.
authors.forename: Tom D
authors.initials: TD
authors.lastname: Green
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University Greenville, NC, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University Greenville, NC, USA.
authors.forename: P Darrell
authors.initials: PD
authors.lastname: Neufer
authors.affiliation: Department of Physiology, Brody School of Medicine, East Carolina University Greenville, NC, USA ; East Carolina Diabetes and Obesity Institute, Brody School of Medicine, East Carolina University Greenville, NC, USA.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: McClung
keywords: angiogenesis; ischemia; mitochondria; peripheral arterial disease; skeletal muscle; vascular diseases