Granulocyte-colony stimulating factor enhances muscle proliferation and strength following skeletal muscle injury in rats

Abstract

Insufficiency of skeletal muscle regeneration often impedes the healing process with functional deficiencies and scar formation. We tested the hematopoietic growth factor granulocyte-colony stimulating factor (G-CSF) with respect to its efficacy to improve functional muscle regeneration following skeletal muscle injury in Wistar rats. After crush injury to the left soleus muscle, animals received daily G-CSF (20 mug/kg ip) or vehicle solution (n = 30 per group each). Sham-operated animals without muscle injury served as controls (n = 15). After in vivo assessment of the fast-twitch and tetanic contraction capacity of the soleus muscles at days 4, 7, and 14 post-injury, sampling of muscle tissue served for analysis of satellite cell proliferation [bromodeoxyuridine (BrdU)/laminin and BrdU/desmin double immunohistochemistry] and cell apoptosis (transferase nick-end labeling analysis). Muscle strength analysis revealed recovery of contraction forces to 26 +/- 2, 35 +/- 3, and 53 +/- 3% (twitch force) and to 20 +/- 3, 24 +/- 2, and 37 +/- 2% (tetanic force) within the 14-day observation period in vehicle-treated animals. In contrast, G-CSF increased contractile forces with markedly higher values at day 7 (twitch force: 42 +/- 2%; tetanic force: 34 +/- 2%) and day 14 (twitch force: 62 +/- 3%; tetanic force: 43 +/- 3%). This enhancement of muscle function was preceded by a significant increase of satellite cell proliferation (BrdU-positive cells/mm(2): 27 +/- 6 vs. vehicle: 12 +/- 3) and a moderate decrease of cell apoptosis (transferase nick-end labeling-positive cells/mm(2): 11 +/- 2 vs. vehicle: 16 +/- 3) at day 4. In conclusion, G-CSF histologically promoted viability and proliferation of muscle cells and functionally enhanced recovery of muscle strength. Thus G-CSF might represent a therapeutic option to optimize the posttraumatic course of muscle tissue healing.

Erythropoietin improves functional and histological recovery of traumatized skeletal muscle tissue

“…Upon a 20-min stabilization period after completion of surgery, in vivo microscopy of the soleus muscle was performed, as previously described for the EDL. [14][15][16][17] To consider the heterogeneous morphology of the traumatized muscle, a classification system, as recently published by our group 18 was used, considering three zones. Zone 1 (z1) was defined as the central muscle area with entrance of the neurovascular structures.…”

“…Thus, muscle regeneration might benefit from adjunct pharmacological strategies, like application of G-CSF 18 and EPO, presumably through mobilization of cells, which will subsequently help to regenerate more intensely and rapidly [38][39][40] or through extracellular signals. 5 In line with this view, EPO caused an increase not only of the number of BrdU-positive satellite cells but also of interstitial cells with finally improved muscle contraction capacity when compared to vehicle-treated injured animals.…”

Magnetic Targeting of Human Peripheral Blood CD133+Cells for Skeletal Muscle Regeneration

“…1 Previous studies have examined the use of drugs, cytokines, cells, and gene therapy attempted to improve muscle recovery. [2][3][4][5][6][7][8][9][10] Recently, we showed that transplantation of human peripheral blood CD133-expressing cells (CD133 + cells) inhibits fibrosis and improves muscle regeneration after skeletal muscle laceration. 11 Human blood CD133 + cells are wellsuited for clinical applications, because collecting these cells is safe, with limited ethical problems.…”

G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy

“…In our previous screen for myocyte differentiationpromoting factors 6,7 , we noted markedly elevated expression of granulocyte colony-stimulating factor receptor (G-CSFR, encoded by csf3r) in the developing somite 8 . Furthermore, G-CSFR was transiently expressed in regenerating myocytes of adult injured skeletal muscle, and extrinsic G-CSF supported short-term muscle regeneration in cardiotoxin-induced skeletal muscle injury 9 and crush injury 10 . However, although we found high G-CSFR expression in regenerating immature myocytes, whether G-CSFR would be expressed in SCs and whether G-CSF signalling would affect the SC population in skeletal muscle remain unclear.…”