Denervation-Induced Activation of the Ubiquitin-Proteasome System Reduces Skeletal Muscle Quantity Not Quality.

Cory W Baumann,Haiming M Liu,Ladora V Thompson,Ashok Kumar

doi:10.1371/journal.pone.0160839

Cory W Baumann, Haiming M Liu + Show 2 more

Open Access

https://doi.org/10.1371/journal.pone.0160839

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Journal: PloS one	Publication Date: Aug 11, 2016
Citations: 17	License type: CC BY 4.0

Affiliation: University of Minnesota Medical Center

Abstract

It is well known that the ubiquitin-proteasome system is activated in response to skeletal muscle wasting and functions to degrade contractile proteins. The loss of these proteins inevitably reduces skeletal muscle size (i.e., quantity). However, it is currently unknown whether activation of this pathway also affects function by impairing the muscle’s intrinsic ability to produce force (i.e., quality). Therefore, the purpose of this study was twofold, (1) document how the ubiquitin-proteasome system responds to denervation and (2) identify the physiological consequences of these changes. To induce soleus muscle atrophy, C57BL6 mice underwent tibial nerve transection of the left hindlimb for 7 or 14 days (n = 6–8 per group). At these time points, content of several proteins within the ubiquitin-proteasome system were determined via Western blot, while ex vivo whole muscle contractility was specifically analyzed at day 14. Denervation temporarily increased several key proteins within the ubiquitin-proteasome system, including the E3 ligase MuRF1 and the proteasome subunits 19S, α7 and β5. These changes were accompanied by reductions in absolute peak force and power, which were offset when expressed relative to physiological cross-sectional area. Contrary to peak force, absolute and relative forces at submaximal stimulation frequencies were significantly greater following 14 days of denervation. Taken together, these data represent two keys findings. First, activation of the ubiquitin-proteasome system is associated with reductions in skeletal muscle quantity rather than quality. Second, shortly after denervation, it appears the muscle remodels to compensate for the loss of neural activity via changes in Ca2+ handling.

Highlights

Skeletal muscle atrophy can occur from a variety of stressors, which include inflammation, mechanical unloading, metabolic stress and neural inactivity
Contractile deficits were observed when expressed relative to muscle size, indicating the muscle’s intrinsic ability to contract was impaired at these later time points [25, 26]. It is generally accepted loss of muscle quantity following denervation is due to the ubiquitin-proteasome system, it is currently unknown whether muscle quality is affected soon after an episode of increased proteolysis mediated by this pathway
To assess how the ubiquitin-proteasome system responded to denervation, we used Western blot analysis to determine content of several key proteins implicated in this pathway (Figs 1 and 2)

Summary

Introduction

Skeletal muscle atrophy can occur from a variety of stressors, which include inflammation, mechanical unloading, metabolic stress and neural inactivity. These stressors are often a result of clinical conditions or chronic diseases such as limb immobilization, bed rest, cachexia, neurodegeneration and aging [1,2,3,4]. Under these situations, there is an imbalance between. The increased rate of proteolysis is mediated through the autophagy-lysosome and ubiquitin-proteasome systems [4, 7, 8], with the latter reported to be the primary degradation pathway in skeletal muscle [9, 10]

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