Skeletal Muscle Atrophy Induced by Diabetes Is Mediated by Non-Selective Channels and Prevented by Boldine
Journal
Biomolecules
ISSN
2218-273X
Date Issued
2023
Author(s)
Luis A. Cea
Walter Vásquez
Romina Hernández-Salinas
Alejandra Z. Vielma
Mario Castillo-Ruiz
Victoria Velarde
Magdiel Salgado
Juan C. Sáez
Type
Resource Types::text::journal::journal article
URL Institutional Repository
Abstract
<jats:p>Individuals with diabetes mellitus present a skeletal muscle myopathy characterized by atrophy. However, the mechanism underlying this muscular alteration remains elusive, which makes it difficult to design a rational treatment that could avoid the negative consequences in muscles due to diabetes. In the present work, the atrophy of skeletal myofibers from streptozotocin-induced diabetic rats was prevented with boldine, suggesting that non-selective channels inhibited by this alkaloid are involved in this process, as has previously shown for other muscular pathologies. Accordingly, we found a relevant increase in sarcolemma permeability of skeletal myofibers of diabetic animals in vivo and in vitro due to de novo expression of functional connexin hemichannels (Cx HCs) containing connexins (Cxs) 39, 43, and 45. These cells also expressed P2X7 receptors, and their inhibition in vitro drastically reduced sarcolemma permeability, suggesting their participation in the activation of Cx HCs. Notably, sarcolemma permeability of skeletal myofibers was prevented by boldine treatment that blocks Cx43 and Cx45 HCs, and now we demonstrated that it also blocks P2X7 receptors. In addition, the skeletal muscle alterations described above were not observed in diabetic mice with myofibers deficient in Cx43/Cx45 expression. Moreover, murine myofibers cultured for 24 h in high glucose presented a drastic increase in sarcolemma permeability and levels of NLRP3, a molecular member of the inflammasome, a response that was also prevented by boldine, suggesting that, in addition to the systemic inflammatory response found in diabetes, high glucose can promote the expression of functional Cx HCs and activation of the inflammasome in skeletal myofibers. Therefore, Cx43 and Cx45 HCs play a critical role in myofiber degeneration, and boldine could be considered a potential therapeutic agent to treat muscular complications due to diabetes.</jats:p>
Subjects
calcium atrophy
;
connexins
;
hemichannel blocker
;
sarcolemma permeability
;
animals
;
connexin 43
;
connexins
;
diabetes mellitus, experimental
;
glucose
;
inflammasomes
;
mice
;
muscle, skeletal
;
muscular atrophy
;
rats
;
boldine
;
calcium
;
connexin 39
;
connexin 43
;
connexin 45
;
cryopyrin
;
gap junction protein
;
inflammasome
;
malonaldehyde
;
purinergic p2x7 receptor
;
unclassified drug
;
boldine
;
connexin 43
;
gap junction protein
;
glucose
;
inflammasome
;
animal cell
;
animal experiment
;
animal model
;
animal tissue
;
article
;
blood vessel reactivity
;
brain cortex
;
calcium signaling
;
confocal microscopy
;
connexon
;
controlled study
;
diabetic complication
;
gene expression
;
glucose blood level
;
glycemic index
;
immunocytochemistry
;
immunofluorescence
;
immunoreactivity
;
male
;
muscle atrophy
;
nonhuman
;
permeability
;
protein expression
;
rat
;
sarcolemma
;
sarcolemma permeability
;
skeletal muscle
;
streptozotocin-induced diabetes mellitus
;
upregulation
;
animal
;
complication
;
experimental diabetes mellitus
;
metabolism
;
mouse
;
muscle atrophy
;
skeletal muscle