Abstract
To determine whether glutamine (Gln) reduces the ratio of oxidized to total glutathione (GSSG/GSH) and extracellular signal-regulated kinase (ERK1/2) activation in dystrophic muscle. Four-week old mdx mice, an animal model for Duchenne muscular dystrophy and control (C57BL/10) received daily intraperitoneal injections of l-Gln (500 mg/kg/d) or 0.9% NaCl for 3 d. GSH and GSSG concentrations in gastrocnemius were measured using a standard enzymatic recycling procedure. Free amino acid concentrations in gastrocnemius were determined by ion exchange chromatography. Phosphorylated protein levels of ERK1/2 in quadriceps were examined using Western Blot. l-Gln decreased GSSG and GSSG/GSH (an indicator of oxidative stress). This was associated with decreased ERK1/2 phosphorylation. Muscle free Gln, glutamate (Glu), and the sum (Gln + Glu) were higher in mdx versus C57BL/10, at the basal level. Exogenous Gln decreased muscle free Glu and Gln + Glu in mdx only, whereas Gln was not affected. In conclusion, exogenous Gln reduces GSSG/GSH and ERK1/2 activation in dystrophic skeletal muscle of young mdx mice, which is associated with decreased muscle free Glu and Gln + Glu. This antioxidant protective mechanism provides a molecular basis for Gln's antiproteolytic effect in Duchenne muscular dystrophy children.
Highlights
Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease resulting from the absence of dystrophin
Because skeletal muscle plays a central role in Gln metabolism and whole body Gln exchange is decreased in DMD [21], we examined the effect of exogenous Gln on muscle-free amino acid concentrations
Body weight was significantly lower in mdx mice versus agematched wild-type C57BL/10 controls, regardless of whether they were treated with 0.9% sodium chloride (NaCl) (NaCl-MDX: 10.5 Ϯ 0.5 g vs. NaCl-C57: 17.0 Ϯ 0.3 g; p Ͻ 0.0001) or L-Gln (GLNMDX: 10.4 Ϯ 0.3 g vs. GLN-C57: 16.0 Ϯ 0.7 g; p Ͻ 0.0001)
Summary
Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease resulting from the absence of dystrophin. Oxidative stress could contribute to muscle-wasting by regulating specific cell signaling pathways leading to increased proteolysis [5]. Antioxidants can improve muscle health by protecting cells from oxidative stress and reducing muscle necrosis in mdx mice (an animal model of DMD) (8 –11). Increased ERK1/2 activation was reported in skeletal muscle of mdx mice [10,16], which was further increased in response to mechanical stress [4]. The primary objective of the present study is to test whether exogenous Gln reduces the ratio of GSSG/GSH [the major regulator of the cellular redox potential and a widely used indicator of oxidative stress [20]] in skeletal muscle of mdx mice. Since oxidative stress mediates activation of MAPK (ERK1/2) and NF-B transactivation [13], we determined the effect of Gln on this pathway. Because skeletal muscle plays a central role in Gln metabolism (as the main producer and exporter of Gln) and whole body Gln exchange is decreased in DMD [21], we examined the effect of exogenous Gln on muscle-free amino acid concentrations
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