The physiological response of protease inhibition in dystrophic muscle

Abstract

Duchenne muscular dystrophy (DMD) is caused by the production of a non-functional dystrophin gene product and a failure to accumulate functional dystrophin protein in muscle cells. This leads to membrane instability, loss of Ca(2+) homoeostasis and widespread cellular injury. Associated with these changes are increased protease activities in a variety of proteolytic systems. As such, there have been numerous investigations directed towards determining the therapeutic potential of protease inhibition. In this review, evidence from genetic and/or pharmacological inhibition of proteases as a treatment strategy for DMD is systematically evaluated. Specifically, we review the potential roles of calpain, proteasome, caspase, matrix metalloproteinase and serine protease inhibition as therapeutic approaches for DMD. We conclude that despite early results to the contrary, inhibition of calpain proteases is unlikely to be successful. Conversely, evidence suggests that inhibition of proteasome, matrix metalloproteinases and serine proteases does appear to decrease disease severity. An important caveat to these conclusions, however, is that the fundamental cause of DMD, dystrophin deficiency, is not corrected by this strategy. Hence, this should not be viewed as a cure, but rather, protease inhibitors should be considered for inclusion in a therapeutic cocktail. Physiological Relevance. Selective modulation of protease activity has the potential to profoundly change intracellular physiology resulting in a possible treatment for DMD. However, alteration of protease activities could also lead to worsening of disease progression by promoting the accumulation of substrates in the cell. The balance of benefit and potential damage caused by protease inhibition in human DMD patients is largely unexplored.

Disease-proportional proteasomal degradation of missense dystrophins

“…Although proteasome inhibition by MG132 in the mdx mouse restored the amino-terminal fragment of dystrophin translated up to the premature stop codon (44), prolonged treatment with MG132 resulted in no improvement of muscle function (46). It has therefore been hypothesized that proteasome inhibition of nonsense dystrophin may treat some of the symptoms of dystrophinopathy such as decreased DGC expression but does not treat the primary cause of disease (48). Our data demonstrate that proteasome inhibition restores full-length, missense dystrophin to WT levels.…”

Immunoproteasome in animal models of Duchenne muscular dystrophy

“…Although these general proteasome inhibitors show some promise in the attenuation of muscle deterioration, two major caveats exist that include lack of specificity for the subtypes of proteasome and proteasome inhibition-induced toxicity (Hollinger and Selsby 2013). Inhibitors that selectively target proteasome subtypes that are responsible for the deterioration in muscle quality would be the logical choice to overcome these caveats.…”

Cathepsin S Contributes to the Pathogenesis of Muscular Dystrophy in Mice

“…Currently there is no cure for DMD, and although gene therapy to restore dystrophin expression is a promising concept, it remains in the distant future (6). Thus, it will be critical to develop novel pharmacologic therapies that address key aspects of disease pathogenesis, such as increased protease activity (7,8).…”

“…Numerous studies have demonstrated that increased activity of select proteases in the skeletal muscle of mouse models of muscular dystrophy, such as the calpains and matrix metalloproteinases, contributes to tissue histopathology (7,14). For example, genetic inhibition of a broad class of serine proteases achieved by overexpressing the inhibitor Serpina3n in skeletal muscle attenuated dystrophic disease in two mouse models of muscular dystrophy (15).…”