Increased myofibrillar protein catabolism in Duchenne muscular dystrophy measured by 3-methylhistidine excretion in the urine.

McKeran, R O; Halliday, D.; Purkiss, P.

doi:10.1136/jnnp.40.10.979

Cited by 66 publications

(20 citation statements)

References 12 publications

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“…These higher rates of MHC synthesis are consistent with the previously reported high turnover rate of myofibrillar proteins (assessed by 3-methylhistidine and creatinine excretion) in DMD (4,35,36), mixed-muscle proteins in the mdx mouse (32), and the FSR of mixed-muscle protein in DMD and Becker dystrophy (42). We furthermore showed a clear rise in MHC synthesis in these subjects in response to oxandrolone.…”

Section: Discussionsupporting

confidence: 79%

Oxandrolone enhances skeletal muscle myosin synthesis and alters global gene expression profile in Duchenne muscular dystrophy

Balagopal

Olney

Mougey³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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(DMD) involves an imbalance between the rates of synthesis and degradation of muscle proteins. Although previous studies have suggested that oxandrolone may be beneficial in DMD, the mechanism of action of oxandrolone on muscle in DMD remains unclear. To address these issues, we combined stable isotope studies and gene expression analysis to measure the fractional synthesis rate of myosin heavy chain (MHC), the key muscle contractile protein, the transcript levels of the isoforms of MHC, and global gene expression profiles in four children with DMD before and after 3 mo of treatment with oxandrolone. Gastrocnemius muscle biopsies and blood samples were collected during the course of a primed 6-h continuous infusion of L-[U-13 C]leucine on two separate occasions, before and after the 3-mo treatment with oxandrolone (0.1 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ). Gene expression analysis was done with microarrays and RT-qPCR. In response to the treatment, MHC synthesis rate increased 42%, and this rise was accounted for, at least in part, by an upregulation of the transcript for MHC8 (perinatal MHC). Gene expression data suggested a decrease in muscle regeneration as a consequence of oxandrolone therapy, presumably because of a decrease in muscle degeneration. These findings suggest that 1) oxandrolone has a powerful protein anabolic effect on a key contractile protein and 2) larger and longer-term studies are warranted to determine whether these changes translate into meaningful therapy for these patients. microarray; stable isotope; mass spectrometry DUCHENNE MUSCULAR DYSTROPHY (DMD) is a severe and progressive form of human muscular dystrophy with a lethal outcome. Although the absence of the protein dystrophin, which is part of a glycoprotein complex located on the intracellular surface of the cellular membrane, was identified as the molecular basis of the disease (25, 28), and despite advances in our understanding of dystrophin function, the precise pathogenesis of the severe muscle damage remains unclear. The most striking manifestations of this disorder are loss of skeletal muscle mass and strength, resulting in severe disability. Previous studies in DMD have suggested that the loss of muscle is likely the result of an imbalance between muscle protein synthesis and degradation (18,42). In DMD, dystrophin deficiency is present in muscle from fetal life onward. However, the loss of muscle is progressive. The progressive nature of the muscle loss implies that there are crucial secondary factors that compound the problems caused by dystrophin deficiency. The gradual loss of regenerating capacity of muscle, which depends on protein synthesis, may be an important factor in this pathogenetic process (18,41,42).The absence of a cure for DMD underscores the importance of adjunctive therapeutic strategies. A recent study by Fenichel et al. (13) suggested an ameliorative effect of oxandrolone, an oral synthetic analog of testosterone, on muscle strength in DMD. Although a subsequent study by the same group did not find a significant ch...

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Section: Discussionsupporting

confidence: 79%

Oxandrolone enhances skeletal muscle myosin synthesis and alters global gene expression profile in Duchenne muscular dystrophy

Balagopal

Olney

Mougey³

et al. 2006

American Journal of Physiology-Endocrinology and Metabolism

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“…Previous investigations on muscle tissue from DMD patients (11)(12)(13)(14)(15)(16)(17) have reported increases in lysosomal protease activity, whereas the results reported here show that total acid autoproteolysis as well as a number of specific lysosomal enzymes are unchanged in DMD fibroblasts. Indeed, one report (13) has shown, contrary to our results on DMD fibroblasts, that DAP-I activity is increased in DMD muscle.…”

Section: Discussioncontrasting

confidence: 56%

“…A major obstacle in biochemical studies of dystrophic muscle has been the extensive secondary changes that occur in the degenerating skeletal muscle which serve to obscure the primary error of metabolism. Thus, there are reports of alterations in the levels of DMD skeletal muscle lipids (2,3), adenylate cyclase activity (4)(5)(6), activity of the sarcotubular system (7), protein synthesis (8), plasma membrane structure (9,10) and the activity of several lysosomal proteases (11)(12)(13)(14)(15)(16)(17). The fact that nonmuscle tissues are also affected clinically, although less critically, has suggested that the primary error might also be expressed in other organ systems (1).…”

Section: Introductionmentioning

confidence: 99%

Decreased Lysosomal Dipeptidyl Aminopeptidase I Activity in Cultured Human Skin Fibroblasts in Duchenne's Muscular Dystrophy

Gelman¹,

Papa²,

Davis³

et al. 1980

J. Clin. Invest.

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A B S T R A C T Several lysosomal enzymes were assayed in cultured human skin fibroblasts from patients with Duchenne's muscular dystrophy (DMD) and age-and sex-matched control patients (N). The activity of four glycosidases, cathepsin B, and total autoproteolysis at pH 4.0 were unchanged between the groups, but dipeptidyl aminopeptidase I (DAP-I, or cathepsin C) in the DMD cells was found to be only 30% as active as in the control cells (P < 0.003). This difference is not the result of a redistribution or loss of enzyme during homogenization because the difference occurs in all homogenate fractions. DAP-I activity existing in N and DMD fibroblasts behaves identically with respect to activation by chloride ion, activation by the sulfhydryl reducing agent dithiothreitol, changes in hydrogen ion concentration (pH), changes in substrate concentration (i.e., apparent Km values), and changes in temperature (i.e., apparent activation energies). Mixtures of N and DMD cell sonicates display an additivity in DAP-I activity. These results support the conclusion that the catalytic function of the DAP-I molecule is equivalent between N and DMD fibroblasts, and that the decrease in tissuespecific DAP-I activity probably results from the fact that fewer enzyme molecules are present in the DMD cells. These results are also an indication that these nonmuscle cells are expressing some of the phenotypic aspects of the genetic defect in DMD. Cultured human skin fibroblasts may therefore be a useful cellular model in DMD research.

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“…Furthermore, the available evidence indicates that the rapid loss of muscle protein and skeletal muscle mass that occurs during various muscle pathologies, such as the muscular dystrophies (McKeran et al, 1977;Ballard et al, 1979;Li, 1980;Warnes et al, 1981;Yoshikawa and Masaki, 1981), myasthenia gravis (Warnes et al, 1981), denervation (Goldberg, 1969b), phorbol diester treatment (West and Holtzer, 1982), and blockage of muscle membrane Na + channels (Crisona and Strohman, 1983), is due primarily to a greatly increased rate of muscle protein degradation with little change or even a slight increase in rate of muscle protein synthesis.…”

Section: Chaptermentioning

confidence: 98%

Skeletal Muscle Proteases and Protein Turnover

Goll

Kleese

Szpacenko

1989

Animal Growth Regulation

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Increased myofibrillar protein catabolism in Duchenne muscular dystrophy measured by 3-methylhistidine excretion in the urine.

Cited by 66 publications

References 12 publications

Oxandrolone enhances skeletal muscle myosin synthesis and alters global gene expression profile in Duchenne muscular dystrophy

Oxandrolone enhances skeletal muscle myosin synthesis and alters global gene expression profile in Duchenne muscular dystrophy

Decreased Lysosomal Dipeptidyl Aminopeptidase I Activity in Cultured Human Skin Fibroblasts in Duchenne's Muscular Dystrophy

Skeletal Muscle Proteases and Protein Turnover

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