Muscle wasting in muscular dystrophy: Decreased protein synthesis or increased degradation?

Abstract

The cause of the muscular dystrophies remains unknown. Recent publications summarize current thoughts on pathogenesis 162, 631. Because of their relatively high incidence and severity, Duchenne dystrophy and myotonic dystrophy have received the greatest attention. Although the primary defect:; in these disorders are obscure, a feature common to all muscular dystrophies is loss of skeletal muscle, which must arise because of an imbalance between muscle protein synthesis and degradation. The mechanisms of muscle protein turnover are currently under intensive study, and approaches have recently been developed for their investigation in patients with neuromuscular disease /23, 601. Further, since agents are now available that may alter protein synthesis or degradarion {ll, 37,47, 48,65, 681, there is some hope of modifying the course of human neuromuscular disease. 'The importance of correctly describing and understanding the processes involved in cell necrosis and regeneration is highlighted by a paper in this issue of Annalr of Neurology 1741.The relevance of much of the following discussion depends upon the reliability of the methods used to measure the components of protein turnover. We will not, however, further discuss the technical problems involved except to say that we believe protein synthlesis in muscle is best measured in vivo or in perfused !jystems by methods that utilize constant infusion /45] or large flooding doses of tracer agents [18], and that tissue culture and isolated muscle systems may give unreliable results. Regrettably, there are no good direct methods of measuring muscle protein degradation, especially in living human beings. Nevertheless, in a discussion of the effects of disease on protein turnover, measurements made in vivo in humans and animals carry the most conviction. (For a discussion of the pros and cons of various methods, see 128, 731.)The factors controlling muscle protein turnover theoretically may produce their effects by altering either synthesis or degradation of protein. In skeletal muscle, however, protein synthesis is clearly the modulated process that is of primary regulatory importance during both the rapid increases that occur with feeding C34, 591 and with induced muscle hypertrophy 121, 28, 341and also during starvation, diabetes, and chronic corticosteroid treatment 145, 46, 551. The situation as regards muscle protein degradation is less clear because of the methodological difficulties in estimating degradation, but evidence is accumulating 1461 that in most circumstances which entail alteration of muscle mass, protein degradation simply adapts to changes in synthesis in a way that effectively limits the extent of the change, i.e., so-called anabolic and catabolic degradation 1431. Muscle Protein Synthesis in Human BeingsThe use of stable isotopes has allowed measurement of muscle protein synthesis in humans. This work was pioneered by Halliday and McKeran 1261, who used "N-labeled lysine delivered by constant infusion over periods lasting up to 12 hours and measu...

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

“…In the early stages of the disease, accelerated regeneration of muscle allows for near-normal function. It is felt that it is the steady loss of regenerative capacity that results in the longterm decline in these patients (18,41,42). Consistent with this, Haslett et al (21) and Chen et al (9) compared global transcript levels from DMD muscle with those from normal muscle and found an overall upregulation of genes associated with muscle regeneration.…”

“…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.…”

“…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.…”

“…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 gradual loss of regenerating capacity of muscle, which depends on protein synthesis, may be an important factor in this pathogenetic process (18,41,42).…”