The effect of acid sphingomyelinase inhibitor on oxidative stress, advance glycation end products and myosin phenotype of rat soleus muscle under conditions of functional unloading
https://doi.org/10.29413/ABS.2025-10.1.13
Abstract
Introduction. Functional unloading of muscles is accompanied by slow-to-fast transformation of muscle myosin phenotype, an increase in acid sphingomyelinase (ASM) activity, ceramide, reactive oxygen species (ROS), and advanced glycation end products (AGEs). The association of sphingolipids, AGEs-associated processes and muscle plasticity has not been studied.
The aim. To assess the relationship of ASM and ceramide-associated increase in ROS to the AGEs-dependent pathway regulating the expression of various myosin heavy chains (MyHC) isoforms during 7-day functional unloading of rat m. soleus, and to evaluate the efficacy of the FIASMA drug in preventing muscle phenotype change.
Methods. White male rats were subjected to 7-day hindlimb suspension (HS) combined with administration of the acid sphingomyelinase inhibitor amitriptyline. Fluorescence microscopy was used to detect the levels of ASM, ceramide, MyHC isoforms, ROS, NADPH oxidase 2 (NOX2), MyoD1 (myoblast determination protein 1), AGEs and their receptors (RAGE, receptor for advanced glycation endproducts) in the soleus muscle. Western blotting was used for detection of NOX2, RAGE and AGEs-modified proteins in muscle homogenates. The changes in MyoD1 level in myonuclei were studied ex vivo by incubating the muscle with exogenous AGEs.
Results. Unloading led to a decrease in the muscle mass and fiber diameter, transformation of myosin phenotype, an increase in ASM, ceramide, ROS, NOX2, AGEs, RAGE and nuclear MyoD1 content. NOX2 and AGEs-modified proteins did not change. Amitriptyline mitigated the loss of muscle mass and fiber diameter reduction, decreased fast to slow shift. It also decreased ASM, ceramide, ROS, RAGE, and mionuclear MyoD1. Muscle incubation with exogenous AGEs increased in MyoD1 in myonuclei.
Conclusion. ASM activation during soleus muscle unloading contributes to the MyoD1-related slow-to-fast myosin transformation associated with ROS overproduction and RAGE signaling.
About the Authors
V. A. ProtopopovRussian Federation
Vladimir A. Protopopov – Postgraduate at the Department of Pathological Physiology and Immunology,
Kommunarov str. 281, Izhevsk 426056
A. V. Sekunov
Russian Federation
Alexey V. Sekunov – Teaching Assistant at the Department of Pathological Physiology and Immunology,
Kommunarov str. 281, Izhevsk 426056
A. M. Mugizov
Russian Federation
Aidar M. Mugizov – Student,
Kommunarov str. 281, Izhevsk 426056
I. V. Svidersky
Russian Federation
Ilya V. Svidersky – Student,
Kommunarov str. 281, Izhevsk 426056
I. G. Bryndina
Russian Federation
Irina G. Bryndina – Dr. Sc. (Med.), Professor, Head of the Department of Pathological Physiology and Immunology,
Kommunarov str. 281, Izhevsk 426056
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Review
For citations:
Protopopov V.A., Sekunov A.V., Mugizov A.M., Svidersky I.V., Bryndina I.G. The effect of acid sphingomyelinase inhibitor on oxidative stress, advance glycation end products and myosin phenotype of rat soleus muscle under conditions of functional unloading. Acta Biomedica Scientifica. 2025;10(1):123-135. (In Russ.) https://doi.org/10.29413/ABS.2025-10.1.13