Cytoplasmic HDAC4 regulates the membrane repair mechanism in Duchenne muscular dystrophy

Journal of Cachexia, Sarcopenia and Muscle

Laura Forcina¹  Viviana Moresi¹  Alessandro Lambridis¹  Dario Coletti¹  Silvia Di Francescantonio¹  Nicoletta Marroncelli¹  Sergio Adamo¹  Giorgia Cavioli¹  Alessandra Renzini¹  Claudia Giampietri²  Sergio Valente³  Antonello Mai³  Eros Di Giorgio⁴  Claudio Brancolini⁴  Francesca De Santa⁵  Alessandra Magenta⁶ 

[1]Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Unit of Histology and Medical Embryology Sapienza University of Rome Rome Italy

[2]Department of Anatomy, Histology, Forensic Medicine and Orthopedics, Unit of Human Anatomy Sapienza University of Rome Rome Italy

[3]Department of Drug Chemistry and Technologies Sapienza University of Rome Rome Italy

[4]Department of Medicine Università degli Studi di Udine Udine Italy

[5]Institute of Biochemistry and Cell Biology (IBBC) National Research Council (CNR) Rome Italy

[6]Institute of Translational Pharmacology (IFT) National Research Council (CNR) Rome Italy

关键词: Duchenne muscular dystrophy;    HDAC4;    HDACi;    Muscle necroptosis;    Membrane repair mechanism;    Satellite cells;   

DOI  :  10.1002/jcsm.12891

来源: DOAJ

【 摘 要 】

Abstract Background Histone deacetylase 4 (HDAC4) is a stress‐responsive factor that mediates multiple cellular responses. As a member of class IIa HDACs, HDAC4 shuttles between the nucleus and the cytoplasm; however, HDAC4 cytoplasmic functions have never been fully investigated. Duchenne muscular dystrophy (DMD) is a genetic, progressive, incurable disorder, characterized by muscle wasting, which can be treated with the unspecific inhibition of HDACs, despite this approach being only partially effective. More efficient strategies may be proposed for DMD only after the different HDAC members will be characterized. Methods To fully understand HDAC4 functions, we generated dystrophic mice carrying a skeletal muscle‐specific deletion of HDAC4 (mdx;KO mice). The progression of muscular dystrophy was characterized in mdx and age‐matched mdx;KO mice by means of histological, molecular, and functional analyses. Satellite cells (SCs) from these mice were differentiated in vitro, to identify HDAC4 intrinsic functions influencing the myogenic potential of dystrophic SCs. Gain‐of‐function experiments revealed the cytoplasmic functions of HDAC4 in mdx;KO muscles. Results Histone deacetylase 4 increased in the skeletal muscles of mdx mice (~3‐fold; P < 0.05) and of DMD patients (n = 3, males, mean age 13.3 ± 1.5 years), suggesting that HDAC4 has a role in DMD. Its deletion in skeletal muscles importantly worsens the pathological features of DMD, leading to greater muscle fragility and degeneration over time. Additionally, it impairs SC survival, myogenic potential, and muscle regeneration, ultimately compromising muscle function (P < 0.05–0.001). The impaired membrane repair mechanism in muscles and SCs accounts for the mdx;KO phenotype. Indeed, the ectopic expression of Trim72, a major player in the membrane repair mechanism, prevents SC death (~20%; P < 0.01) and increases myogenic fusion (~40%; P < 0.01) in vitro; in vivo it significantly reduces myofibre damage (~10%; P < 0.005) and improves mdx;KO muscle function (P < 0.05). The mdx;KO phenotype is also fully rescued by restoring cytoplasmic levels of HDAC4, both in vitro and in vivo. The protective role of HDAC4 in the cytoplasm of mdx;KO muscles is, in part, independent of its deacetylase activity. HDAC4 expression correlates with Trim72 mRNA levels; furthermore, Trim72 mRNA decays more rapidly (P < 0.01) in mdx;KO muscle cells, compared with mdx ones. Conclusions Histone deacetylase 4 performs crucial functions in the cytoplasm of dystrophic muscles, by mediating the muscle repair response to damage, an important role in ensuring muscle homeostasis, probably by stabilizing Trim72 mRNA. Consequently, the cytoplasmic functions of HDAC4 should be stimulated rather than inhibited in muscular dystrophy treatments, a fact to be considered in future therapeutic approaches.

【 授权许可】

Unknown