1. Beyond atrophy: redox mechanisms of muscle dysfunction in chronic inflammatory disease.
- Author
-
Reid MB and Moylan JS
- Subjects
- Animals, Chronic Disease, Humans, Inflammation pathology, Inflammation physiopathology, Inflammation Mediators metabolism, Muscle Weakness pathology, Muscle Weakness physiopathology, Muscular Atrophy pathology, Muscular Atrophy physiopathology, Oxidation-Reduction, Receptors, Tumor Necrosis Factor, Type I metabolism, Signal Transduction, Tumor Necrosis Factor-alpha metabolism, Inflammation metabolism, Muscle Contraction, Muscle Strength, Muscle Weakness metabolism, Muscle, Skeletal metabolism, Muscular Atrophy metabolism, Oxidative Stress, Reactive Oxygen Species metabolism
- Abstract
Chronic inflammatory diseases such as heart failure, cancer and arthritis have secondary effects on skeletal muscle that cause weakness and exercise intolerance. These symptoms exacerbate illness and make death more likely. Weakness is not simply a matter of muscle atrophy. Functional studies show that contractile dysfunction, i.e. a reduction in specific force, makes an equally important contribution to overall weakness. The most clearly defined mediator of contractile dysfunction is tumour necrosis factor (TNF). TNF serum levels are elevated in chronic disease, correlate with muscle weakness, and are a predictor of morbidity and mortality. Research is beginning to unravel the mechanism by which TNF depresses specific force. TNF acts via the TNFR1 receptor subtype to depress force by increasing cytosolic oxidant activity. Oxidants depress myofibrillar function, decreasing specific force without altering calcium regulation or other aspects of myofibrillar mechanics. Beyond these concepts, the intracellular mechanisms that depress specific force remain undefined. We do not know the pathway by which receptor-ligand interaction stimulates oxidant production. Nor do we know the type(s) of oxidants stimulated by TNF, their intracellular source(s), or their molecular targets. Investigators in the field are pursuing these issues with the long-term goal of preserving muscle function in individuals afflicted by chronic disease.
- Published
- 2011
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