A substituted dextran enhances muscle fiber survival and regeneration in ischemic and denervated rat EDL muscle

Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration surrounded by a thin zone of peripheral surviving musc le fibers. Muscle regeneration is a complex phenomenon in which many agents interact, such as growth factors and heparan sulfate components of the ext racellular matrix. We have shown that synthetic polymers, called RGTA las r egenerating agents), which imitate the heparan sulfates, are able to stimul ate tissue repair when applied at the site of injury. In crushed muscles, R GTA were found to accelerate both regeneration and reinnervation. In vitro, RGTA act as protectors and potentiators of various heparin binding growth factors (HBGF). It was postulated that in vivo their tissue repair properti es were due in part to an increase of bioavailability of endogenously relea sed HBGF. In the present work, we show that ischemic and denervated EDL mus cle treated by a unique injection of RGTA differs from the control after 1 wk in several aspects: 1) the epimysial postinflammatory reaction is inhibi ted and the area of fibrotic tissue among fibers is reduced; 2) the periphe ral zone, as measured by the number of intact muscle fibers, was increased by more than twofold; and 3) In the central zone, RGTA enhances the regener ation of the muscle fibers as well as muscle revascularization. These resul ts suggest that RGTA both protects muscle fibers from degeneration and pres erves the differentiated state of the surviving fibers. For the first time it is demonstrated that a functionalized polymeric compound can prevent som e of the damage resulting from muscle ischemia. RGTA may therefore open a n ew therapeutic approach for muscle fibrosis and other postischemic muscle p athologies.