Increased Turnover of Muscle Contractile Proteins in Duchenne Muscular Dystrophy as Assessed by 3-Methylhistidine and Creatinine Excretion

Ballard, F. J.; Tomas, F. M.; Stern, L. M.

doi:10.1042/cs0560347

Cited by 53 publications

(7 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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

View full text Add to dashboard Cite

(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...

show abstract

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

View full text Add to dashboard Cite

show abstract

“…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

View full text Add to dashboard Cite

“…1-10) is shown in dures applied and by disparities in the fibroblast populations investigated by the two groups as discussed elsewhere (20). On the basis of our findings, it seems very likely that DMD fibroblasts in vitro express the same defect in protein degradation that was demonstrated in muscle tissue of DMD patients (1,2) and in animal models of this disorder (3,26 (29). An 80%o enhanced hydroxylation of proline residues in collagen types I and III resulting in a 2-fold increase in the degradation of collagen types I and III has been described for DMD fibroblasts in vitro (14).…”

Section: Methodsmentioning

confidence: 92%

“…The primary genetic defect of this disorder has not been defined; dystrophy of skeletal and cardiac muscles is considered to be the result of an abnormal protein metabolism (1)(2)(3). Analyses of the primary and/or secondary biochemical defects in degenerating muscle in DMD in vivo have been hampered by secondary changes-e.g., concomitant regeneration and degeneration of myoblasts, fibroblasts, and fat cells (1).…”

mentioning

confidence: 99%

Differential degradation of [35S]methionine polypeptides in Duchenne muscular dystrophy skin fibroblasts in vitro.

Rodemann¹,

Bayreuther²

1986

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Rates of protein turnover have been measured in three normal and three Duchenne muscular dystrophy (DMD) skin fibroblast cell lines. Cell populations were analyzed at identical states with regard to cell number, state of topoinhibition, and cumulative population doublings (CPD). Net protein synthesis measured by the incorporation of [35SSmethionine in an 18-hr pulse was reduced by an average of 34%; degradation of total cellular protein measured after an 18-hr pulse with [35S]methionine and a 24-hr chase was enhanced by an average of 50% in DMD fibroblasts. Twodimensional gel electrophoresis analyses revealed that the breakdown of the majority of [35S]methionine polypeptides was markedly increased in DMD fibroblasts. Quantitative determinations of the differential degradation rates of 10 selected proteins in the tropomyosin region of two-dimensional gels were undertaken by scintillation counting and computer analyses. In three series of experiments, the degradation of the 10 proteins in DMD fibroblasts was enhanced by individual polypeptides between 12.0% and 151.2% as measured by scintillation counting or between 0.8% and 128% as determined by computer analyses.Duchenne muscular dystrophy (DMD) is an X-chromosomelinked recessive disorder, characterized by a progressive muscle degeneration in the primary organs of manifestation, the skeletal and cardiac muscles. The primary genetic defect of this disorder has not been defined; dystrophy of skeletal and cardiac muscles is considered to be the result of an abnormal protein metabolism (1-3). Analyses of the primary and/or secondary biochemical defects in degenerating muscle in DMD in vivo have been hampered by secondary changes-e.g., concomitant regeneration and degeneration of myoblasts, fibroblasts, and fat cells (1). The secondary changes make the selection of an appropriate reference base and of a representative control in vivo difficult.Numerous cellular and biochemical abnormalities have also been demonstrated in nerve, erythrocyte, and fibroblast cells in DMD patients (1, 4, 5). DMD skin fibroblast populations in vitro express a variety of syndrome-specific cellbiological (6-10), and biochemical (11-17) (20).In the present study, we analyzed net protein synthesis and degradation of total cellular protein and of individual proteins in DMD and normal skin fibroblasts by two-dimensional gel electrophoresis. We will provide evidence that in DMD skin fibroblasts the majority of proteins are affected by a decreased net synthesis and an enhanced degradation. Analyses ofthe degradation of individual [35S]methionine polypeptides in the tropomyosin region of two-dimensional gels revealed a significant polypeptide-specific increase in the rates of degradation in DMD fibroblasts. MATERIALS AND METHODSCell Cultures. Skin fibroblast populations of three male patients (6-15 yr old) with advanced to very advanced manifestations of the DMD syndrome and of three agematched normal male probands were established from skin biopsies as described elsewhere (14). Three DMD ...

show abstract

Increased Turnover of Muscle Contractile Proteins in Duchenne Muscular Dystrophy as Assessed by 3-Methylhistidine and Creatinine Excretion

Cited by 53 publications

References 21 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

Skeletal Muscle Proteases and Protein Turnover

Differential degradation of [35S]methionine polypeptides in Duchenne muscular dystrophy skin fibroblasts in vitro.

Contact Info

Product

Resources

About