A novel PAI-1 inhibitor prevents ageing-related muscle fiber atrophy

https://doi.org/10.1016/j.bbrc.2020.10.089Get rights and content
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Highlights

  • Novel PAI-1 inhibitor, TM5484 was examined as a therapy for preventing sarcopenia.

  • TM5484 treatment caused significantly greater calf muscle force in older mice.

  • TM5484-treated older mice showed thicker muscle fibers than younger mice.

  • Treatment with TM5484 induced genes involved in muscle growth and regeneration.

  • Oral PAI-1 inhibitors present a promising therapy for preventing sarcopenia.

Abstract

Sarcopenia is among the most common medical problems of the aging population worldwide and a major social concern. Here, we explored the therapeutic potential of TM5484, a novel orally available PAI-1 inhibitor, to prevent sarcopenia. The sarcopenic phenotypes of the calf muscle of 12- and 6-month-old middle-aged mice were compared. Although significant decline of isometric gastrocnemius muscle force was detected in the older untreated mice, those administered TM5484 had significantly greater calf muscle force, as determined using isometric measurements by electrical stimulation. Histological analysis indicated that cross-sectional gastrocnemius muscle fibers in untreated older mice were thinner than those in younger mice; however, TM5484-treated group showed thicker fibers than younger mice. Treatment with TM5484 for 6 months enhanced Igf1, Atrogin-1, Mt-Co1, and Chrna1 mRNA expression in the mice gastrocnemius muscle, with increased serum IGF-1 concentration. TM5484 induced dose-dependent Igf1, Atrogin-1, and Chrna1 expression in C2C12 myoblastic cells, confirming cell autonomous effect. Further, the presence of plasmin for 72 h caused significantly increased Igf1 expression in C2C12 cells. These findings suggest that oral PAI-1 inhibitors represent a promising therapeutic candidate for preventing sarcopenia progression in humans.

Keywords

Igf1
PAI-1 inhibitor
TM5484
Sarcopenia

Abbreviations

BBB
blood-brain barrier
GH
growth hormone
HE
hematoxylin and eosin
MAFbx
muscle atrophy F-box
NMJ
neuromuscular junction
PAI-1
plasminogen activator inhibitor-1
qRT-PCR
quantitative reverse transcription PCR
ROS
reactive oxygen species
t-PA
tissue-type plasminogen activator
u-PA
urokinase-type plasminogen activator

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