Duchenne muscular dystrophy (DMD) is a lethal, Xlinked disorder associated with dystrophin deficiency that results in chronic inflammation, sarcolemma damage, and severe skeletal muscle degeneration. Recently, the use of L-arginine , the substrate of nitric oxide synthase (nNOS), has been proposed as a pharmacological treatment to attenuate the dystrophic pattern of DMD. However, little is known about signaling events that occur in dystrophic muscle with L-arginine treatment. Considering the implication of inflammation in dystrophic processes, we asked whether L-arginine inhibits inflammatory signaling cascades. We demonstrate that L-arginine decreases inflammation and enhances muscle regeneration in the mdx mouse model. Classic stimulatory signals, such as proinflammatory cytokines interleukin-1␤, interleukin-6, and tumor necrosis factor-␣, are significantly decreased in mdx mouse muscle, resulting in lower nuclear factor (NF)-B levels and activity. NF-B serves as a pivotal transcription factor with multiple levels of regulation; previous studies have shown perturbation of NF-B signaling in both mdx and DMD muscle. Moreover, L-arginine decreases the activity of metalloproteinase (MMP)-2 and MMP-9, which are transcriptionally activated by NF-B. We show that the inhibitory effect of L-arginine on the NF-B/MMP cascade reduces ␤-dystroglycan cleavage and translocates utrophin and nNOS throughout the sarcolemma. Collectively, our results clarify the molecular events by which L-arginine promotes muscle membrane integrity in dystrophic muscle and suggest that NF-B-related signaling cascades could be potential therapeutic targets for DMD management. (Am J Pathol

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The aim of this study was to validate a noninvasive tension-time index (TT) for all the inspiratory muscles estimated from the measurement of mouth occlusion pressure (P0.1), i.e., TT of inspiratory muscles (TTmus = PI/PImax x TI/TT, where PI is mean inspiratory pressure, PImax is maximal PI, TI is time of muscle contraction, and TT is total time of respiratory cycle) compared with TT of the diaphragm (TTdi = Pdi/Pdimax x TI/TT, where Pdi is mean transdiaphragmatic pressure and Pdimax is maximal Pdi). PI was estimated as PI = 5 P0.1 x TI. Eleven patients with chronic obstructive pulmonary disease and seven normal subjects were studied at rest in the sitting position. After 5 min of steady state, we measured breathing pattern, gastric and esophageal pressures, Pdi, mean inspiratory transpulmonary pressure swing, PImax, and Pdimax. By linear regression analysis, significant positive correlations were found between PI and mean inspiratory transpulmonary pressure swing, PI and Pdi, PImax and Pdimax, and PI/PImax and Pdi/Pdimax, with P < 0.001 for all subjects combined. These led to the highly significant correlation between TTmus and TTdi for all subjects combined (TTmus = 2.1 TTdi + 0.012; r = 0.97; P < 0.001) and for patients only (TTmus = 2.0 TTdi + 0.024; r = 0.97; P < 0.001). Therefore, patterns of breathing that lie near fatigue thresholds can be identified with TTmus or TTdi. In conclusion, noninvasive and clinically easily determined TTmus seems valid for situating patients of chronic obstructive pulmonary disease in reference to the inspiratory muscle fatigue.

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