Age- and time-dependent mitochondrial genotoxic and myopathic effects of beta-guanidinopropionic acid, a creatine analog, on rodent skeletal muscles
Age- and time-dependent mitochondrial genotoxic and myopathic effects of beta-guanidinopropionic acid, a creatine analog, on rodent skeletal muscles
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DOI：
10.1007/s11357-022-00667-4
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发表时间：
2022-09-30
期刊：
影响因子：
5.6
通讯作者：
Wanagat, Jonathan
中科院分区：
文献类型：
--
作者：
Herbst, Allen;Aiken, Judd M.;Wanagat, Jonathan
β-胍基丙酸（GPA）是一种肌酸类似物，建议用于治疗高血压，糖尿病和肥胖症，主要表现在老年人中。GPA的一个显著副作用是诱导线粒体DNA缺失突变。我们假设mtDNA缺失有助于肌肉衰老，并使用GPA的突变促进作用来研究mtDNA缺失对具有不同衰老脆弱性的肌肉的影响。大鼠从14或30月龄开始用GPA处理长达4个月。我们检查了四头肌和长收肌肌肉，因为四头肌表现出严重的年龄引起的退化，而长收肌保持不变。GPA降低身体和肌肉质量和mtDNA拷贝数，同时增加mtDNA缺失频率。在四头肌中观察到的年龄和GPA处理之间的相互作用在长收肌中未观察到。GPA在短短4周内就对线粒体产生了负面影响。GPA处理加剧了四头肌（一种年龄敏感的肌肉）的mtDNA缺失和肌肉老化表型，而长收肌则幸免于难。GPA已被提议用于与年龄相关的疾病，但GPA的药效学随年龄而不同，包括对mtDNA缺失的有害诱导，这是一种线粒体基因毒性应激，在最容易衰老的肌肉中很明显。需要进一步的研究来确定GPA对高血压，糖尿病和肥胖的拟议益处是否超过有害的线粒体和肌病副作用。
Beta-guanidinopropionic acid (GPA) is a creatine analog suggested as a treatment for hypertension, diabetes, and obesity, which manifest primarily in older adults. A notable side effect of GPA is the induction of mitochondrial DNA deletion mutations. We hypothesized that mtDNA deletions contribute to muscle aging and used the mutation promoting effect of GPA to examine the impact of mtDNA deletions on muscles with differential vulnerability to aging. Rats were treated with GPA for up to 4 months starting at 14 or 30 months of age. We examined quadriceps and adductor longus muscles as the quadriceps exhibits profound age-induced deterioration, while adductor longus is maintained. GPA decreased body and muscle mass and mtDNA copy number while increasing mtDNA deletion frequency. The interactions between age and GPA treatment observed in the quadriceps were not observed in the adductor longus. GPA had negative mitochondrial effects in as little as 4 weeks. GPA treatment exacerbated mtDNA deletions and muscle aging phenotypes in the quadriceps, an age-sensitive muscle, while the adductor longus was spared. GPA has been proposed for use in age-associated diseases, yet the pharmacodynamics of GPA differ with age and include the detrimental induction of mtDNA deletions, a mitochondrial genotoxic stress that is pronounced in muscles that are most vulnerable to aging. Further research is needed to determine if the proposed benefits of GPA on hypertension, diabetes, and obesity outweigh the detrimental mitochondrial and myopathic side effects.