Accession Number:

ADA586854

Title:

Modulation of Stem Cell Differentiation and Myostatin as an Approach to Counteract Fibrosis in Muscle Dystrophy and Regeneration After Injury. Addendum

Descriptive Note:

Final rept. 1 Mar 2011-29 Feb 2012

Corporate Author:

CHARLES R DREW UNIV OF MEDICINE AND SCIENCE LOS ANGELES CA

Personal Author(s):

Report Date:

2012-03-01

Pagination or Media Count:

204.0

Abstract:

We have investigated in the notexin-injured skeletal muscle of the aged mdx mouse a novel therapeutic approach for Duchenne s muscular dystrophy DMD based on the implantation of muscle-derived stem cells MDSC, and the putative stimulation of their repair capacity by inhibition of myostatin Mst expression andor activity, for the alleviation of fibrotic and fatty degeneration of the note xininjured dystrophic muscle. MDSC from the wild type mouse WT MDSC, the myostatin knock-out mouse Mst KO MDSC, and the mdx mouse mdx MDSC were compared. Concurrent pharmacological interventions were also tested with WT MDSC on skeletal muscle, and other tissues. We showed the repair capacity of MDSC to counteract fibrosis and the resulting dysfunction in several non-skeletal muscle tissues in other rat and mouse models, the pro-fibrotic effects of myostatin, and the antifibrotic effects of nitric oxide donors molsidomine, PDE 5 inhibitors sildenafil, and antioxidants allopurinol, alone or in combination with WT MDSC. We found that WT MDSC are considerably myogenic in cell culture and stimulate muscle repair after injury in the aged mdx mouse, but that Mst KO MDSC are unable to form myotubes in vitro. However, their myogenic capacity is recovered in vivo under the influence of the myostatin host tissue environment, presumably by reactivation of key genes originally silenced in these cells. Our ongoing studies suggest that although myofibroblast generation may impair muscle tissue repair by WT MDSC, this may be counteracted with molsidomine, but not by antioxidants, and that the MDSCmolsidomine combination stimulates angiogenesis in the severely necrotic muscle of mice with limb ischemia.

Subject Categories:

  • Anatomy and Physiology
  • Medicine and Medical Research

Distribution Statement:

APPROVED FOR PUBLIC RELEASE