Alves Paula K N, Cruz André, Silva William J, Melazzo Afonso M, Labeit Siegfried, Adams Volker, Moriscot Anselmo S
Department of Anatomy, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Faculty for Clinical Medicine Mannheim of the University of Heidelberg, Institute for Integrative Pathophysiology, Mannheim, Germany.
Muscle Nerve. 2025 Jul;72(1):139-148. doi: 10.1002/mus.28411. Epub 2025 Apr 4.
INTRODUCTION/AIMS: We previously demonstrated that leucine supplementation significantly reduces histone deacetylase 4 (HDAC4) expression induced by hindlimb immobilization, thereby attenuating the increase in HDAC4 protein levels and nuclear accumulation. In this study, we investigated the impact of supraphysiological HDAC4 levels on skeletal muscle and the inhibitory potential of leucine in this scenario.
A total of 64 male Wistar rats were used in this study and subjected to electroporation of the soleus muscle with or without a plasmid overexpressing HDAC4 mRNA, followed by hindlimb immobilization and leucine supplementation (1.35 g/kg) for 7 days.
Our findings revealed that HDAC4 overexpression alone led to soleus atrophy, resulting in a 23% decrease in mass, a 31% reduction in whole muscle cross-sectional area (CSA), and a 17% decrease in fiber CSA. These reductions were further exacerbated by hindlimb immobilization, with decreases of 50%, 46%, and 34%, respectively. Moreover, leucine supplementation protected against soleus atrophy and preserved soleus fiber CSA by 17%. This protective effect was accompanied by a 57% reduction in HDAC4-positive nuclear localization in immobilized rats overexpressing HDAC4.
Our results indicate that HDAC4 forced expression can alone induce skeletal muscle atrophy. In addition, our results indicate that leucine is dominant in blocking HDAC4 signaling and highlight the use of this amino acid as a therapeutic tool in conditions involving skeletal muscle atrophy.
引言/目的：我们之前证明，补充亮氨酸可显著降低后肢固定诱导的组蛋白去乙酰化酶4（HDAC4）表达，从而减弱HDAC4蛋白水平的升高和核积累。在本研究中，我们调查了超生理水平的HDAC4对骨骼肌的影响以及亮氨酸在这种情况下的抑制潜力。
本研究共使用64只雄性Wistar大鼠，对其比目鱼肌进行电穿孔，分为导入或未导入过表达HDAC4 mRNA的质粒两组，随后进行后肢固定，并补充亮氨酸（1.35 g/kg），持续7天。
我们的研究结果显示，单独的HDAC4过表达导致比目鱼肌萎缩，肌肉质量下降23%，全肌横截面积（CSA）减少31%，肌纤维CSA减少17%。后肢固定进一步加剧了这些减少，分别下降了50%、46%和34%。此外，补充亮氨酸可防止比目鱼肌萎缩，并使比目鱼肌纤维CSA保持在17%。这种保护作用伴随着在过表达HDAC4的固定大鼠中，HDAC4阳性核定位减少57%。
我们的结果表明，强制表达HDAC4可单独诱导骨骼肌萎缩。此外，我们的结果表明，亮氨酸在阻断HDAC4信号传导中起主导作用，并突出了这种氨基酸在涉及骨骼肌萎缩的病症中作为治疗工具的用途。
