Plasminogen activator inhibitor type 1 up-regulation is associated with skeletal muscle atrophy and associated fibrosis.

TY - JOUR

T1 - Plasminogen activator inhibitor type 1 up-regulation is associated with skeletal muscle atrophy and associated fibrosis.

AU - Naderi, Jasmin 

AU - Bernreuther, Christian

AU - Grabinski, Nicole

AU - Putman, Charles T

AU - Henkel, Birgit

AU - Bell, Gordon

AU - Glatzel, Markus

AU - Sultan, Karim

PY - 2009

Y1 - 2009

N2 - Muscle wasting remains a feature of many diseases and is counteracted by anabolic supplementation or exercise. Persisting atrophy-inducing conditions can be complicated by skeletal muscle fibrosis, which leads to functional impairment. Identification of early mechanisms that initiate atrophy-induced fibrosis may reveal novel targets for therapy or diagnosis. Therefore, we investigated changes in the expression of genes involved in extracellular matrix homeostasis during glucocorticoid-induced atrophy of myotubes and compared them with insulin-like growth factor-1-induced hypertrophy. Obtained results were verified in rat gastrocnemius muscle that was exposed to microgravity by space flight for 2 weeks. Myostatin and atrogin-1 mRNA levels reflected the magnitude of atrophy. Despite differential induction of these negative muscle mass regulators, no major changes in matrix metalloproteinases-2, -9, and -14 mRNAs or their physiological inhibitors could be detected in either atrophy model. In contrast, transcript levels of plasminogen activator inhibitor type 1 (PAI-1) was dramatically increased in atrophic myotubes and microgravity-exposed rat gastrocnemius muscle, while plasminogen activators remained unaltered. In contrast to atrophy, no increase in PAI-1 mRNA levels could be detected in rat hindlimb that was electrically stimulated for 21 days. Furthermore, a strong increase in PAI-1 mRNA levels was identified in skeletal muscle of patients with neurogenic muscle atrophy. Our study suggests that increased PAI-1 expression in atrophic skeletal muscle may lead to muscle fibrosis by reducing plasmin generation.

AB - Muscle wasting remains a feature of many diseases and is counteracted by anabolic supplementation or exercise. Persisting atrophy-inducing conditions can be complicated by skeletal muscle fibrosis, which leads to functional impairment. Identification of early mechanisms that initiate atrophy-induced fibrosis may reveal novel targets for therapy or diagnosis. Therefore, we investigated changes in the expression of genes involved in extracellular matrix homeostasis during glucocorticoid-induced atrophy of myotubes and compared them with insulin-like growth factor-1-induced hypertrophy. Obtained results were verified in rat gastrocnemius muscle that was exposed to microgravity by space flight for 2 weeks. Myostatin and atrogin-1 mRNA levels reflected the magnitude of atrophy. Despite differential induction of these negative muscle mass regulators, no major changes in matrix metalloproteinases-2, -9, and -14 mRNAs or their physiological inhibitors could be detected in either atrophy model. In contrast, transcript levels of plasminogen activator inhibitor type 1 (PAI-1) was dramatically increased in atrophic myotubes and microgravity-exposed rat gastrocnemius muscle, while plasminogen activators remained unaltered. In contrast to atrophy, no increase in PAI-1 mRNA levels could be detected in rat hindlimb that was electrically stimulated for 21 days. Furthermore, a strong increase in PAI-1 mRNA levels was identified in skeletal muscle of patients with neurogenic muscle atrophy. Our study suggests that increased PAI-1 expression in atrophic skeletal muscle may lead to muscle fibrosis by reducing plasmin generation.

M3 - SCORING: Zeitschriftenaufsatz

VL - 175

SP - 763

EP - 771

JO - AM J PATHOL

JF - AM J PATHOL

SN - 0002-9440

IS - 2

M1 - 2

ER -