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Inducible nitric oxide synthase in skeletal muscle of patients with chronic heart failure
U N Riede1, U Förstermann, H Drexler
1Department of Pathology, University of Freiburg, Germany.
Objectives:
The expression and localization of inducible nitric oxide (NO) synthase (NOS II) was evaluated as a source of NO which has been shown to affect muscle contraction.
Background:
Advanced stages of chronic heart failure are associated with systemic activation of cytokines which have been shown to stimulate the expression of NOS II in various cell types, including myocytes. We hypothesized that systemic cytokine activation could lead to expression of NOS II in skeletal muscle of patients with chronic heart failure.
Methods:
Skeletal muscle specimens were obtained by percutaneous needle biopsy in six normal volunteers and eight patients with heart failure (New York Heart Association class III). Electron microscopy immunocytochemistry (immunogold labeling) with specific anti-NOS antibodies was utilized to elucidate the intracellular localization of NOS II and neuronal NO synthase (NOS I) in myocytes of skeletal muscle. Reverse transcriptase, competitive polymerase chain reaction (PCR) was applied to quantify NOS II mRNA in skeletal muscle.
Results:
Inducible nitric oxide synthase was readily expressed in the cytosol of skeletal muscle myocytes; NOS I expression was sparse. Polymerase chain reaction results indicated that NOS II gene expression is increased in patients with chronic heart failure.
Conclusions:
Inducible NO synthase is expressed in human skeletal muscle and its gene expression is increased in patients with severe heart failure. Given the experimental evidence that NO can attenuate contractile performance of skeletal muscle and can mediate muscle wasting, an increased local production of NO in skeletal muscle by NOS II may have important implications for patients with severe heart failure.
Insights
Inducible nitric oxide synthase (NOS II) is found in human skeletal muscle. Its gene expression increases in patients with severe heart failure, potentially impacting muscle function.
Area of Science:
- Physiology
- Molecular Biology
- Pathology
Background:
- Chronic heart failure involves systemic cytokine activation.
- Cytokines stimulate inducible nitric oxide synthase (NOS II) in various cell types.
- This study investigated NOS II expression in skeletal muscle of heart failure patients.
Purpose of the Study:
- To evaluate the expression and localization of inducible nitric oxide synthase (NOS II) in skeletal muscle.
- To determine if NOS II is a source of nitric oxide (NO) affecting muscle contraction in heart failure.
- To test the hypothesis that systemic cytokine activation leads to NOS II expression in skeletal muscle of heart failure patients.
Main Methods:
- Skeletal muscle biopsies from normal volunteers and heart failure patients.
- Immunoelectron microscopy (immunogold labeling) for NOS II and NOS I localization in myocytes.
- Quantitative analysis of NOS II mRNA using competitive reverse transcriptase polymerase chain reaction (PCR).
Main Results:
- Inducible nitric oxide synthase (NOS II) was expressed in the cytosol of skeletal muscle myocytes.
- Neuronal nitric oxide synthase (NOS I) expression was sparse.
- NOS II gene expression was significantly increased in heart failure patients compared to controls.
Conclusions:
- Inducible nitric oxide synthase (NOS II) is expressed in human skeletal muscle.
- Increased NOS II gene expression in severe heart failure patients suggests elevated local nitric oxide (NO) production.
- Increased NO in skeletal muscle may contribute to impaired muscle contractility and wasting in heart failure.