Overexpression of osteoactivin protects skeletal muscle from severe degeneration caused by long-term denervation in mice.
We have previously shown that osteoactivin, a type I membrane glycoprotein expressed in myofibers, upregulated expression of matrix metalloprotease (MMP)-3 and MMP-9 in fibroblasts infiltrated denervated skeletal muscle in mice. To address whether osteoactivin-mediated increase in MMPs in skeletal muscle is useful for regeneration of denervated skeletal muscle, we subjected osteoactivin-transgenic mice to long-term denervation for 70 or 90 days. Long-term denervation caused severe degeneration of myofibers and fibrosis in skeletal muscle of wild-type mice. However, overexpression of osteoactivin protected skeletal muscle from such changes. Infiltration of fibroblast-like cells and collagen deposition were sustained at low levels after long-term denervation in skeletal muscle of osteoactivin-transgenic mice. This cytoprotective effect of osteoactivin was supported by the expression of regeneration/degeneration-associated genes in the gastrocnemius muscle during denervation. Denervation significantly upregulated the expression of anti-fibrotic genes, such as glypican-1 and decorin-1, in the gastrocnemius muscle of osteoactivin-transgenic mice, compared with wild-type mice. In contrast, overexpression of osteoactivin caused a significant reduction in denervation-induced expression of elongation factor 1A-1, an indicator for the persistence of degenerated cells. Our results suggest that an osteoactivin-mediated increase in MMPs in skeletal muscle might be useful for protecting injured muscle from fibrosis, leading to full regeneration after denervation.
Furochi
Harumi
H
Department of Nutritional Physiology, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Tamura
Seiko
S
Takeshima
Kayo
K
Hirasaka
Katsuya
K
Nakao
Reiko
R
Kishi
Kyoichi
K
Nikawa
Takeshi
T
D000818:Animals; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D015870:Gene Expression; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000235:genetics; D008562:Membrane Glycoproteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D009121:Muscle Denervation / Q000009:adverse effects*; D018482:Muscle, Skeletal / Q000294:innervation / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012038:Regeneration
D017931:DNA Primers; C503043:Gpnmb protein, rat; D008562:Membrane Glycoproteins; D011994:Recombinant Proteins; D019278:Matrix Metalloproteinase 3