| First Author | Mázala DA | Year | 2015 |
| Journal | Am J Physiol Cell Physiol | Volume | 308 |
| Issue | 1 | Pages | C33-40 |
| PubMed ID | 25298424 | Mgi Jnum | J:223583 |
| Mgi Id | MGI:5659786 | Doi | 10.1152/ajpcell.00267.2013 |
| Citation | Mazala DA, et al. (2015) The role of proteases in excitation-contraction coupling failure in muscular dystrophy. Am J Physiol Cell Physiol 308(1):C33-40 |
| abstractText | Duchenne muscular dystrophy (DMD) is one of the most frequent types of muscular dystrophy. Alterations in intracellular calcium (Ca(2+)) handling are thought to contribute to the disease severity in DMD, possibly due to the activation of Ca(2+)-activated proteases. The purpose of this study was twofold: 1) to determine whether prolonged excitation-contraction (E-C) coupling disruption following repeated contractions is greater in animals lacking both dystrophin and utrophin (mdx/Utr(-/-)) compared with mice lacking only dystrophin (mdx); and 2) to assess whether protease inhibition can prevent E-C coupling failure following repeated tetani in these dystrophic mouse models. Excitation-contraction coupling was assessed using Fura-2 ratio, as an index of intracellular free Ca(2+) concentration, in response to electrical stimulation of single muscle fibers from the flexor digitorum brevis muscle. Resting Fura-2 ratio was higher in dystrophic compared with control (Con) fibers, but peak Fura-2 ratios during stimulation were similar in dystrophic and Con fibers. One hour after a series of repeated tetani, peak Fura-2 ratios were reduced by 30 +/- 5.6%, 23 +/- 2%, and 36 +/- 3.1% in mdx, mdx/Utr(+/-), and mdx/Utr(-/-), respectively, with the greatest reduction in mdx/Utr(-/-) fibers (P < 0.05). Protease inhibition attenuated this decrease in peak Fura-2 ratio. These data indicate that E-C coupling impairment after repeated contractions is greatest in fibers lacking both dystrophin and utrophin and that prevention of protease activation can mitigate the prolonged E-C coupling impairment. These data further suggest that acute protease inhibition may be useful in reducing muscle weakness in DMD. |
