Expression of transforming growth factor-beta 1 in dystrophic patient muscles correlates with fibrosis. Pathogenetic role of a fibrogenic cytokine.
Duchenne muscular dystrophy is a fatal disorder characterized by progressive muscular weakness, wasting, and severe muscle contractures in later disease stages. Muscle biopsy reveals conspicuous myofiber degeneration and fibrosis substituting muscle tissue. We quantitatively determined mRNA of the potent fibrogenic cytokine transforming growth factor-beta 1 by quantitative PCR in 15 Duchenne muscular dystrophy, 13 Becker muscular dystrophy, 11 spinal muscular atrophy patients, and 16 controls. Higher transforming growth factor-beta 1 expression was greater in Duchenne muscular dystrophy patients than controls (P = 0.012) and Becker patients (P = 0.03). Fibrosis was significantly more prominent in Duchenne muscular dystrophy than Becker muscular dystrophy, spinal muscular atrophy, and controls. The proportion of connective tissue in muscle biopsies increased progressively with age in Duchenne muscular dystrophy patients, while transforming growth factor-beta 1 levels peaked at 2 and 6 yr of age. Transforming growth factor-beta 1 protein was also detected by immunocytochemistry and immunoblotting. Our findings suggest that transforming growth factor-beta 1 stimulates fibrosis in Duchenne muscular dystrophy. Expression of transforming growth factor-beta 1 in the early stages of Duchenne muscular dystrophy may be critical in initiating muscle fibrosis and antifibrosis treatment could slow progression of the disease, increasing the utility of gene therapy.
Bernasconi
P
P
Department of Neuromuscular Diseases C. Besta National Neurological Institute, Milan, Italy.
Torchiana
E
E
Confalonieri
P
P
Brugnoni
R
R
Barresi
R
R
Mora
M
M
Cornelio
F
F
Morandi
L
L
Mantegazza
R
R
D000367:Age Factors; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D003238:Connective Tissue / Q000473:pathology; D016207:Cytokines / Q000502:physiology*; D005355:Fibrosis; D015870:Gene Expression; D006801:Humans; D008969:Molecular Sequence Data; D009132:Muscles / Q000378:metabolism* / Q000473:pathology; D009136:Muscular Dystrophies / Q000145:classification / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000032:analysis; D014897:Spinal Muscular Atrophies of Childhood / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics / Q000502:physiology
D016207:Cytokines; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta