Early Lipid Raft-Related Changes: Interplay between Unilateral Denervation and Hindlimb Suspension.

Irina G Bryndina,Alexey M Petrov,Vladimir A Protopopov,Andrey L Zefirov,Alexey V Sekunov,Maria N Shalagina,Guzalia F Zakirjanova

doi:10.3390/ijms22052239

Abstract

Muscle disuse and denervation leads to muscle atrophy, but underlying mechanisms can be different. Previously, we have found ceramide (Cer) accumulation and lipid raft disruption after acute hindlimb suspension (HS), a model of muscle disuse. Herein, using biochemical and fluorescent approaches the influence of unilateral denervation itself and in combination with short-term HS on membrane-related parameters of rat soleus muscle was studied. Denervation increased immunoexpression of sphingomyelinase and Cer in plasmalemmal regions, but decreased Cer content in the raft fraction and enhanced lipid raft integrity. Preliminary denervation suppressed (1) HS-induced Cer accumulation in plasmalemmal regions, shown for both nonraft and raft-fractions; (2) HS-mediated decrease in lipid raft integrity. Similar to denervation, inhibition of the sciatic nerve afferents with capsaicin itself increased Cer plasmalemmal immunoexpression, but attenuated the membrane-related effects of HS. Finally, both denervation and capsaicin treatment increased immunoexpression of proapoptotic protein Bax and inhibited HS-driven increase in antiapoptotic protein Bcl-2. Thus, denervation can increase lipid raft formation and attenuate HS-induced alterations probably due to decrease of Cer levels in the raft fraction. The effects of denervation could be at least partially caused by the loss of afferentation. The study points to the importance of motor and afferent inputs in control of Cer distribution and thereby stability of lipid rafts in the junctional and extrajunctional membranes of the muscle.

Highlights

Skeletal muscle atrophy is the loss of muscle mass caused by conditions such as disuse, neuromuscular disorders, catabolic conditions and aging
SMase Immunoexpression in the Soleus Muscle of Control (Sham-Operated Rats) and Previously, we found marked upregulation of SMases accompanied by increase in Cer levels in skeletal muscle after 12h hindlimb suspension (HS) [5,14]
Deafferentation of Capssensitive primary afferents (CSPA) much stronger increased Bax in combination with HS, and decreased Bcl-2 in disused muscle. These results suggest that apoptotic protein response is unregulated due to combination of HS with denervation and especially CSPA deafferentation

Summary

Introduction

Skeletal muscle atrophy is the loss of muscle mass caused by conditions such as disuse, neuromuscular disorders, catabolic conditions and aging. Denervation, are widely used to simulate muscle disuse in experiments on rodents [1,2]. Both HS and denervation lead to the development of muscle atrophy, there is evidence that, in some aspects, they induce different underlying pathophysiological mechanisms [3]. Early events in response to HS and denervation can be crucial for triggering different chains of pathological cascade. Revealing these initial events may provide information indispensable for developing specific therapeutic approaches

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