Mitchell Wayne, Pharaoh Gavin, Tyshkovskiy Alexander, Campbell Matthew, Marcinek David J, Gladyshev Vadim N
Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Department of Radiology, University of Washington, Seattle, Washington, USA.
Aging Cell. 2025 Mar 13:e70026. doi: 10.1111/acel.70026.
Aging-related decreases in cardiac and skeletal muscle function are strongly associated with various comorbidities. Elamipretide (ELAM), a novel mitochondria-targeted peptide, has demonstrated broad therapeutic efficacy in ameliorating disease conditions associated with mitochondrial dysfunction across both clinical and pre-clinical models. Herein, we investigated the impact of 8-week ELAM treatment on pre- and post-measures of C57BL/6J mice frailty, skeletal muscle, and cardiac muscle function, coupled with post-treatment assessments of biological age and affected molecular pathways. We found that health status, as measured by frailty index, cardiac strain, diastolic function, and skeletal muscle force, is significantly diminished with age, with skeletal muscle force changing in a sex-dependent manner. Conversely, ELAM mitigated frailty accumulation and was able to partially reverse these declines, as evidenced by treatment-induced increases in cardiac strain and muscle fatigue resistance. Despite these improvements, we did not detect statistically significant changes in gene expression or DNA methylation profiles indicative of molecular reorganization or reduced biological age in most ELAM-treated groups. However, pathway analyses revealed that ELAM treatment showed pro-longevity shifts in gene expression, such as upregulation of genes involved in fatty acid metabolism, mitochondrial translation, and oxidative phosphorylation, and downregulation of inflammation. Together, these results indicate that ELAM treatment is effective at mitigating signs of sarcopenia and cardiac dysfunction in an aging mouse model, but that these functional improvements occur independently of detectable changes in epigenetic and transcriptomic age. Thus, some age-related changes in function may be uncoupled from changes in molecular biological age.
与衰老相关的心脏和骨骼肌功能下降与多种合并症密切相关。伊拉米肽（ELAM）是一种新型的线粒体靶向肽，在临床和临床前模型中均已证明在改善与线粒体功能障碍相关的疾病状况方面具有广泛的治疗效果。在此，我们研究了为期8周的伊拉米肽治疗对C57BL/6J小鼠虚弱、骨骼肌和心肌功能的治疗前后测量指标的影响，以及治疗后对生物学年龄和受影响分子途径的评估。我们发现，通过虚弱指数、心脏应变、舒张功能和骨骼肌力量衡量的健康状况会随着年龄的增长而显著下降，其中骨骼肌力量的变化存在性别依赖性。相反，伊拉米肽减轻了虚弱的积累，并能够部分逆转这些下降，治疗引起的心脏应变增加和肌肉抗疲劳能力增强证明了这一点。尽管有这些改善，但在大多数接受伊拉米肽治疗的组中，我们并未检测到表明分子重组或生物学年龄降低的基因表达或DNA甲基化谱的统计学显著变化。然而，通路分析显示，伊拉米肽治疗在基因表达上表现出促长寿的转变，例如参与脂肪酸代谢、线粒体翻译和氧化磷酸化的基因上调，以及炎症相关基因下调。总之，这些结果表明，伊拉米肽治疗在减轻衰老小鼠模型中的肌肉减少症和心脏功能障碍迹象方面是有效的，但这些功能改善的发生与表观遗传和转录组年龄的可检测变化无关。因此，一些与年龄相关的功能变化可能与分子生物学年龄的变化脱钩。
