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Mitochondrial Regulation of the Muscle Microenvironment in Critical Limb Ischemia
Terence E Ryan1, Cameron A Schmidt1, Tom D Green1
1Department 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.
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.
Insights
Critical limb ischemia (CLI) is a severe peripheral arterial disease. Targeting skeletal muscle mitochondria offers a novel therapeutic approach for CLI, addressing muscle damage and improving outcomes.
Area of Science:
- Mitochondrial biology
- Peripheral arterial disease research
- Skeletal muscle physiology
Background:
- Critical limb ischemia (CLI) represents the most severe form of peripheral arterial disease, characterized by chronic limb pain and tissue necrosis.
- Current treatments for CLI are often ineffective, and therapeutic angiogenesis has shown limited success, necessitating novel therapeutic strategies.
- Skeletal muscle myopathies significantly contribute to morbidity and mortality in CLI patients, yet effective muscle-targeted therapies remain elusive.
Purpose of the Study:
- To review the critical role of skeletal muscle in the pathology of CLI.
- To examine the influence of muscle and endothelial cell mitochondria within the ischemic microenvironment.
- To explore the potential of targeting muscle mitochondria as a novel therapeutic strategy for CLI.
Main Methods:
- Literature review focusing on skeletal muscle, mitochondria, and CLI.
- Analysis of the role of mitochondria in cellular energy production and redox balance during ischemia.
- Discussion of therapeutic implications of targeting muscle mitochondria in CLI.
Main Results:
- Skeletal muscle is a key determinant of outcomes in CLI.
- Mitochondria play a crucial role in regulating cellular responses to ischemia within muscle cells.
- Muscle mitochondria are emerging as a promising therapeutic target for CLI.
Conclusions:
- Novel therapeutic strategies are urgently needed for CLI due to the limitations of current interventions.
- Targeting skeletal muscle mitochondria presents a promising avenue for developing effective CLI therapies.
- Understanding the interplay between mitochondria and the ischemic microenvironment is crucial for advancing CLI treatment.
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