Abstract
BackgroundDenervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet.MethodsTo further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle.ResultsAfter an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitin-proteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy.ConclusionsThese results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy.
Highlights
Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy
Skeletal muscles of HDAC4mKO mice lost structural integrity following long-term denervation To delineate the role of Histone deacetylase 4 (HDAC4) in skeletal muscle with a genetic approach following long-term denervation, the sciatic nerve of HDAC4mKO and control mice was cut, and Tibialis anterior (TA) muscles were analyzed over time
Muscle mass evaluation showed that HDAC4mKO mice lost significantly less TA weight if compared with control mice, for the first 2 weeks after denervation, as previously published [31]
Summary
Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Different molecular mechanisms, including the catabolic pathways—e.g., the ubiquitin-proteasome system and autophagy—and oxidative stress (OS), which are normally involved in the maintenance of muscle homeostasis, are activated following muscle denervation, contributing to muscle atrophy [1,2,3]. Initially considered as a non-selective degradation pathway, autophagy plays a role in the selective removal of specific organelles, such as mitochondria (via mitophagy) or protein aggregates. Several proteins, e.g., α-synuclein or aggregateprone proteins, are known to share these two degradative pathways [15,16,17,18], indicating that UPS and autophagy may be interchangeable, depending on cellular necessity. The inhibition of either process has been shown to drive the activation of the other in physiological contexts [19,20,21,22,23]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
