Biological approaches to improve skeletal muscle healing after injury and disease

Abstract

Skeletal muscle injury and repair are complex processes, including well-coordinated steps of degeneration, inflammation, regeneration, and fibrosis. We have reviewed the recent literature including studies by our group that describe how to modulate the processes of skeletal muscle repair and regeneration. Antiinflammatory drugs that target cyclooxygenase-2 were found to hamper the skeletal muscle repair process. Muscle regeneration phase can be aided by growth factors, including insulin-like growth factor-1 and nerve growth factor, but these factors are typically short-lived, and thus more effective methods of delivery are needed. Skeletal muscle damage caused by traumatic injury or genetic diseases can benefit from cell therapy; however, the majority of transplanted muscle cells (myoblasts) are unable to survive the immune response and hypoxic conditions. Our group has isolated neonatal skeletal muscle derived stem cells (MDSCs) that appear to repair muscle tissue in a more effective manner than myoblasts, most likely due to their better resistance to oxidative stress. Enhancing antioxidant levels of MDSCs led to improved regenerative potential. It is becoming increasingly clear that stem cells tissue repair by direct differentiation and paracrine effects leading to neovascularization of injured site and chemoattraction of host cells. The factors invoked in paracrine action are still under investigation. Our group has found that angiotensin II receptor blocker (losartan) significantly reduces fibrotic tissue formation and improves repair of murine injured muscle. Based on these data, we have conducted a case study on two hamstring injury patients and found that losartan treatment was well tolerated and possibly improved recovery time. We believe this medication holds great promise to optimize muscle repair in humans.

Copyright © 2012 Wiley Periodicals, Inc.

Figures

Figure 1

Generalized scheme of myogenic differentiation. Other markers are used by different investigators. (Adapted from Deasy et al., 2001, Blood Cells Mol Dis, 27, 924–933)

Figure 2

Healing process in the skeletal muscle. Several overlapping phases are accompanied by the release of growth factors that modulate regeneration and formation of fibrotic tissue. Use of antifibrotic agents minimizes muscle scarring and leads to better functional outcome.

Figure 3

Schematic of potential scenario of events taking place during cell therapy. Donor stem cells proliferate, differentiate, apoptose, senesce, or more importantly produce trophic factors that would have autocrine and paracrine effects on other donor and host cells. Furthermore, certain factors (e.g., VEGF) promote agniogenesis, which can positively affect other processes.

Figure 4

Hamstring strength in two hamstring injury patients treated with Losartan (affected leg readings are charted in red).