HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

Abstract

Background: Denervation 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. Methods: To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. Results: After 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 ubiquitinproteasome 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. Conclusions: These 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.

Expression Levels of Long Non-Coding RNAs Change in Models of Altered Muscle Activity and Muscle Mass

“…Expression levels of oxidative metabolic genes and extracellular matrix components are also affected in these models [81][82][83]. In addition, the contralateral sham-operated muscles, which are commonly used for the experimental controls in denervation and casting studies [84][85][86][87][88], might undergo hypertrophy to compensate for the immobilized muscles [89]. The proteasome system is also activated in the contralateral-innervated muscles compared with the muscles of non-operated mice [90].…”

HDAC4 Regulates Skeletal Muscle Regeneration via Soluble Factors

“…Therefore, to define HDAC4 functions in adult skeletal muscle, we analyzed muscle regeneration in a mouse line in which HDAC4 deletion is mediated by a Cre-recombinase under the control of the myogenin promoter, i.e., since the embryonic stage E8.5 (HDAC4 mKO mice) ( Cheng et al, 1992 ). This mouse line does not show overt abnormalities in skeletal muscle under physiological conditions ( Moresi et al, 2010 ; Pigna et al, 2018 ). However, 1 week after injury, HDAC4 mKO mice showed smaller regenerating fibers than HDAC4 fl/fl mice, used as controls, by histological analyses ( Figure 2A ).…”

“…To dissect the HDAC4 biological functions in skeletal muscle, excluding SCs in the early phases of differentiation, we generated HDAC4 mKO mice, in which HDAC4 deletion occurs upon myogenin expression. HDAC4 mKO mice do not show skeletal muscle abnormalities at baseline ( Moresi et al, 2010 ; Pigna et al, 2018 ). However, following injury, deletion of HDAC4 in skeletal muscle significantly hampered muscle regeneration.…”

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

“…While the observations reported above suggest that HDAC inhibition could be a useful strategy to counteract muscle atrophy (Figure 1), a note of caution must be introduced, since a recent study reveals that long term inhibition of HDAC4 might be detrimental in conditions such as aging or neuromuscular diseases, unless this is not coupled with other pharmacological interventions such as the adoption of antioxidant treatments [84].…”