3-Methylhistidine excretion as an index of myofibrillar protein catabolism in neuromuscular disease.

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

doi:10.1136/jnnp.42.6.536

Cited by 44 publications

(18 citation statements)

References 28 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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“…Second, rates of muscle-protein synthesis and catabolism in animals, calculated from isotope infusion experiments, show a similar large fall with age [35-371. The situation in Duchenne dystrophy is more controversial. The 3-MeH/creatinine ratio is increased between two-and four-fold, but entirely as a consequence of a very low rate of creatinine excretion [ 17,20,38,39]. However, this low rate and the resultant calculated myofibrillar mass is in general agreement with clinical evaluation, provided allowance is made for infiltration of nonmuscular tissue between myofibrils.…”

Section: A Problem Of Interpretation Arises In Subjectsmentioning

confidence: 90%

3-Methylhistidine as a Measure of Skeletal Muscle Protein Breakdown in Human Subjects: The Case for Its Continued Use

1983

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“…Lukaski et al [18] determined that meat consumption increases 3-MH excretion and that 3 days of a meat-free diet are required to return urinary 3-MH to baseline levels. However, with careful dietary and exercise controls, qualitative inferences can be made concerning skeletal muscle metabolism [14,16,19].…”

Section: Introductionmentioning

confidence: 99%

Liquid carbohydrate/essential amino acid ingestion during a short-term bout of resistance exercise suppresses myofibrillar protein degradation

2006

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3-Methylhistidine excretion as an index of myofibrillar protein catabolism in neuromuscular disease.

Cited by 44 publications

References 28 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

3-Methylhistidine as a Measure of Skeletal Muscle Protein Breakdown in Human Subjects: The Case for Its Continued Use

Liquid carbohydrate/essential amino acid ingestion during a short-term bout of resistance exercise suppresses myofibrillar protein degradation

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