Immunolocalization of Myostatin (GDF-8) Following Musculoskeletal Injury and the Effects of Exogenous Myostatin on Muscle and Bone Healing

Abstract

SummaryThe time course and cellular localization of myostatin expression following musculoskeletal injury are not well understood; therefore, the authors evaluated the temporal and spatial localization of myostatin during muscle and bone repair following deep penetrant injury in a mouse model. They then used hydrogel delivery of exogenous myostatin in the same injury model to determine the effects of myostatin exposure on muscle and bone healing. Results showed that a "pool" of intense myostatin staining was observed among injured skeletal muscle fibers 12-24 hr postsurgery and that myostatin was also expressed in the soft callus chondrocytes 4 days following osteotomy. Hydrogel delivery of 10 or 100 µg/ml recombinant myostatin decreased fracture callus cartilage area relative to total callus area in a dose-dependent manner by 41% and 80% (p<0.05), respectively, compared to vehicle treatment. Myostatin treatment also decreased fracture callus total bone volume by 30.6% and 38.8% (p<0.05), with the higher dose of recombinant myostatin yielding the greatest decrease in callus bone volume. Finally, exogenous myostatin treatment caused a significant dose-dependent increase in fibrous tissue formation in skeletal muscle. Together, these findings suggest that early pharmacological inhibition of myostatin is likely to improve the regenerative potential of both muscle and bone following deep penetrant musculoskeletal injury. (J Histochem Cytochem 60:22-30, 2012)

The skeletal muscle secretome: an emerging player in muscle–bone crosstalk

“…30 Myostatin treatment induces muscle wasting and myostatin deficiency increases muscle mass. We have recently shown that myostatin is highly expressed by injured myofibers following traumatic extremity injury, 37 and that local application of exogenous myostatin increases skeletal muscle fibrosis and inhibits bone repair. 37 These data are consistent with studies referenced above, demonstrating that intact muscle flaps enhance bone repair, whereas coverage of bone injuries with damaged muscle does not have the same positive effects on bone healing.…”

“…We have recently shown that myostatin is highly expressed by injured myofibers following traumatic extremity injury, 37 and that local application of exogenous myostatin increases skeletal muscle fibrosis and inhibits bone repair. 37 These data are consistent with studies referenced above, demonstrating that intact muscle flaps enhance bone repair, whereas coverage of bone injuries with damaged muscle does not have the same positive effects on bone healing. These in vivo data are also consistent with our in vitro studies showing that myostatin treatment suppresses the proliferation and chondrogenic differentiation of bone marrow-derived stromal (stem) cells.…”

Pulsed focused ultrasound treatment of muscle mitigates paralysis-induced bone loss in the adjacent bone: A study in a mouse model

“…The Saline sham group experienced some bone loss in the injected limb. This may potentially be caused by acute inflammation at the injection site (Stei et al 1996;Thuilliez et al 2009), which may have a detrimental effect on bone quality (Elkasrawy et al 2012). …”

The muscle–bone connection

“…12 All of this research points to an important role for myostatin in bone repair. Finally, Dr Hamrick noted that muscle contraction may be one mechanism by which myostain expression can be suppressed; in rats subjected to sciatic nerve stimulation, muscle contractions, especially those of the eccentric variety, were found to reduce the expression of myostatin.…”

“…Dr Hamrick presented his recent data from a mouse fibula osteotomy model, which includes damage to overlying muscle tissue, showing that expression of myostatin in muscle rises both 12 and 24 h after surgery. 12 Other work from Dr Hamrick's group has found recently that mice lacking myostatin exhibit an increase in proliferation of bone marrow stromal cells (BMSCs); conversely, treating those cells with myostatin suppressed BMSC proliferation. 13 In addition, Dr Hamrick has found that, in a cell culture model where cartilage formation is induced from BMSCs, myostatin suppresses chondrogenesis.…”