Optimization and construct validity of approaches to preclinical grip strength testing

IF 8.9 1区 医学 Journal of Cachexia, Sarcopenia and Muscle Pub Date : 2023-08-13 DOI:10.1002/jcsm.13300
Gregory Owendoff, Alissa Ray, Prameela Bobbili, Leatha Clark, Cory W. Baumann, Brian C. Clark, W. David Arnold
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David Arnold","doi":"10.1002/jcsm.13300","DOIUrl":null,"url":null,"abstract":"<p>Grip strength is a robust biomarker showing good reliability<span><sup>1, 2</sup></span> and prediction of negative health outcomes.<span><sup>3, 4</sup></span> Low grip strength is associated with disability and premature death<span><sup>5-9</sup></span> and is more strongly associated with frailty than chronological age.<span><sup>10</sup></span> Accordingly, recent updates to consensus definitions of sarcopenia focus on low grip strength as the primary characteristic as opposed to low muscle mass.<span><sup>11, 12</sup></span> Because rodent models are indispensable tools in aging research, scientists have reverse-translated grip testing as a key outcome in the context of sarcopenia.<span><sup>13-16</sup></span> Serendipitous development of preclinical grip testing has resulted in a variety of protocols that have not been extensively examined and compared.<span><sup>13-15, 17</sup></span> Variability, due to motivation, temperament, and other factors such as pain, is inherent in preclinical behavioural assessments.<span><sup>18</sup></span> Limited research has focused on standardizing preclinical grip testing, validation of methods against other functional measures, and investigating how preclinical grip data compare to data from humans and whether these tests even measure the same construct. Additionally, prior work has not examined between-day reliability of grip testing in rodents. This work was undertaken to inform rigorous preclinical grip testing.</p><p>Differences between clinical and preclinical grip must be considered when reverse translating methods to mice. Clinical grip testing is volitional whereas preclinical testing depends on reflexive responses. Prior clinical studies have consistently shown ICC ≥ 0.80 for repeated grip strength testing.<span><sup>1</sup></span> No data is available regarding the reliability of grip strength methods in mouse models. One study tested grip strength across three successive trials at a single study timepoint (ICC ranging 0.363–0.803) but did not assess reliability across days.<span><sup>24</sup></span> Our study showed that preclinical grip testing methods are less reliable compared to prior clinical studies. Based on CV, all limb grip testing was the most reliable method; based on ICC, bilateral hindlimb and forelimb grip testing were the most reliable methods. Thus, when choosing a method for grip assessment in aged mice where hindlimb assessment is critical, both all limb and bilateral hindlimb methods appear to be the best options for repeatability. Of note, how mice are grasped, tail or scruffing, was not assessed herein, but might impact results. Thus, further work is needed to better refine preclinical grip testing protocols.</p><p>The relationships between grip strength and indices of muscle mass were explored in a clinical cohort to compare these same relationships in mice. The age-related differences in grip strength noted in both our clinical and preclinical age comparisons were more overt as compared with losses of lean/muscle mass. These findings are aligned with the continued evolution of sarcopenia diagnostic criteria, which are increasingly focused on loss of muscle function rather than size/mass.<span><sup>3, 11, 12</sup></span> We found moderately strong relationships between clinical grip strength and DXA estimates of lean mass in humans. The muscles that are recruited during grip testing in mice have not been determined, and thus, we used soleus and gastrocnemius muscle mass as proxy measures of muscle mass. Associations in mice were considerably less robust than in the clinical cohort. However, for select grip methods, associations were comparable. Here, it is important to point out the possibility that large differences in sample sizes and size of mouse muscles versus lean mass in humans could impact correlations.</p><p>Our work provides insight into the construct validity of grip testing in rodents, which shows reasonable overlap with the conceptual elements of clinical grip testing. 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We speculate that in mice, the even lower association between grip strength and muscle mass is due to similar neural impairments but that broader issues related to animal motivation further impact the data.<span><sup>18</sup></span> In addition to correlations with muscle mass, in our preclinical studies, we also used muscle contractility as a non-behavioural, proxy measure of muscle function. We previously showed that these measures are robust indicators of neuromuscular function in aged mouse models.<span><sup>20, 27</sup></span> Muscle contractility showed correlations with all five testing methods, further supporting physiological validity of grip testing in mice.</p><p>In summary, grip strength is a standard method for assessing muscle function in preclinical and clinical studies. This work informs technique, study design, and implementation of preclinical aging studies. 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Abstract

Grip strength is a robust biomarker showing good reliability1, 2 and prediction of negative health outcomes.3, 4 Low grip strength is associated with disability and premature death5-9 and is more strongly associated with frailty than chronological age.10 Accordingly, recent updates to consensus definitions of sarcopenia focus on low grip strength as the primary characteristic as opposed to low muscle mass.11, 12 Because rodent models are indispensable tools in aging research, scientists have reverse-translated grip testing as a key outcome in the context of sarcopenia.13-16 Serendipitous development of preclinical grip testing has resulted in a variety of protocols that have not been extensively examined and compared.13-15, 17 Variability, due to motivation, temperament, and other factors such as pain, is inherent in preclinical behavioural assessments.18 Limited research has focused on standardizing preclinical grip testing, validation of methods against other functional measures, and investigating how preclinical grip data compare to data from humans and whether these tests even measure the same construct. Additionally, prior work has not examined between-day reliability of grip testing in rodents. This work was undertaken to inform rigorous preclinical grip testing.

Differences between clinical and preclinical grip must be considered when reverse translating methods to mice. Clinical grip testing is volitional whereas preclinical testing depends on reflexive responses. Prior clinical studies have consistently shown ICC ≥ 0.80 for repeated grip strength testing.1 No data is available regarding the reliability of grip strength methods in mouse models. One study tested grip strength across three successive trials at a single study timepoint (ICC ranging 0.363–0.803) but did not assess reliability across days.24 Our study showed that preclinical grip testing methods are less reliable compared to prior clinical studies. Based on CV, all limb grip testing was the most reliable method; based on ICC, bilateral hindlimb and forelimb grip testing were the most reliable methods. Thus, when choosing a method for grip assessment in aged mice where hindlimb assessment is critical, both all limb and bilateral hindlimb methods appear to be the best options for repeatability. Of note, how mice are grasped, tail or scruffing, was not assessed herein, but might impact results. Thus, further work is needed to better refine preclinical grip testing protocols.

The relationships between grip strength and indices of muscle mass were explored in a clinical cohort to compare these same relationships in mice. The age-related differences in grip strength noted in both our clinical and preclinical age comparisons were more overt as compared with losses of lean/muscle mass. These findings are aligned with the continued evolution of sarcopenia diagnostic criteria, which are increasingly focused on loss of muscle function rather than size/mass.3, 11, 12 We found moderately strong relationships between clinical grip strength and DXA estimates of lean mass in humans. The muscles that are recruited during grip testing in mice have not been determined, and thus, we used soleus and gastrocnemius muscle mass as proxy measures of muscle mass. Associations in mice were considerably less robust than in the clinical cohort. However, for select grip methods, associations were comparable. Here, it is important to point out the possibility that large differences in sample sizes and size of mouse muscles versus lean mass in humans could impact correlations.

Our work provides insight into the construct validity of grip testing in rodents, which shows reasonable overlap with the conceptual elements of clinical grip testing. In humans, grip is a highly evolved, complex task that imposes great demands on the central nervous system.25 Tests of maximum grip strength require that the human brain modulates recruitment of 19 muscles within the hand and another 20 muscles located in the forearm in a spatially and temporally differentiated pattern. Thus, the force measured during grip strength testing depends not only on activation of muscles that flex the fingers but also on the ability of the nervous system to engage muscles that orient the fingers as well as those that stabilize the hand and wrist. Impairments in the nervous system to fully activate the grip musculature become exacerbated with advancing age (for a review, see Clark and Carson26). Neural impairment likely explains why ~60% of variability in grip strength was explained by muscle mass in humans. We speculate that in mice, the even lower association between grip strength and muscle mass is due to similar neural impairments but that broader issues related to animal motivation further impact the data.18 In addition to correlations with muscle mass, in our preclinical studies, we also used muscle contractility as a non-behavioural, proxy measure of muscle function. We previously showed that these measures are robust indicators of neuromuscular function in aged mouse models.20, 27 Muscle contractility showed correlations with all five testing methods, further supporting physiological validity of grip testing in mice.

In summary, grip strength is a standard method for assessing muscle function in preclinical and clinical studies. This work informs technique, study design, and implementation of preclinical aging studies. It also provides insight into the construct validity of grip strength testing in rodents having reasonable overlap with the conceptual elements of grip strength testing in humans. Our findings suggest a slight edge to the all limb over the bilateral hindlimb method in retest reliability and statistical significance between young and aged mice. Given the clinical significance of grip strength as an indicator of overall health outcomes in older adults, this optimization of grip strength testing techniques in preclinical studies is crucial to the validity and translatability of future preclinical studies exploring the mechanisms of sarcopenia and potential therapeutics to combat aged-related decline in motor function.

This work was supported by funding from NIA/NIH R56AG055795 and R03AG067387 to WDA, R01AG067758 to WDA and BCC, and R01AG044424 to BCC.

The authors declare no conflict of interest.

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临床前握力测试方法的优化和结构有效性。
握力是一种强有力的生物标志物,显示出良好的可靠性1,2,并能预测负面的健康结果。3,4握力低与残疾和过早死亡相关5-9,与实际年龄相比,握力低与身体虚弱的关系更大因此,最近对肌肉减少症的共识定义的更新集中在低握力作为主要特征,而不是低肌肉质量。由于啮齿动物模型是衰老研究中不可或缺的工具,科学家们将握力测试作为肌肉减少症研究的关键结果。13-16临床前握力测试的偶然发展导致了各种尚未被广泛检查和比较的方案。由于动机、性情和其他因素(如疼痛)所引起的可变性是临床前行为评估所固有的有限的研究集中在标准化临床前握力测试,验证其他功能测量方法,调查临床前握力数据如何与人类数据进行比较,以及这些测试是否测量相同的结构。此外,先前的工作没有检查啮齿动物握力测试的日间可靠性。这项工作是为了进行严格的临床前抓地力测试。当对小鼠进行反向翻译时,必须考虑临床和临床前握力之间的差异。临床握力测试是意志性的,而临床前测试则依赖于反射性反应。先前的临床研究一致表明,反复握力测试的ICC≥0.80没有关于握力方法在小鼠模型中的可靠性的数据。一项研究在单个研究时间点(ICC范围为0.363-0.803)连续三次试验中测试了握力,但没有评估跨天的可靠性我们的研究表明,与之前的临床研究相比,临床前握力测试方法不太可靠。基于CV,全肢体抓握力测试是最可靠的方法;基于ICC,双侧后肢和前肢握力测试是最可靠的方法。因此,当选择一种方法来评估老年小鼠的握力时,后肢评估是至关重要的,全肢和双侧后肢方法似乎是重复性的最佳选择。值得注意的是,如何抓住老鼠,尾巴或摩擦,没有评估在这里,但可能会影响结果。因此,需要进一步的工作来更好地完善临床前握力测试方案。在一个临床队列中,我们探讨了握力和肌肉质量指数之间的关系,以比较小鼠中这些相同的关系。在我们的临床和临床前年龄比较中,握力的年龄相关差异与瘦/肌肉质量的损失相比更为明显。这些发现与肌少症诊断标准的持续发展相一致,这些诊断标准越来越关注肌肉功能的丧失,而不是大小/质量。3,11,12我们发现临床握力与DXA对人类瘦质量的估计之间存在中等强度的关系。在小鼠握力测试中招募的肌肉尚未确定,因此,我们使用比目鱼肌和腓肠肌肌肉质量作为肌肉质量的替代测量。与临床队列相比,小鼠中的相关性要弱得多。然而,对于选择的握力方法,关联是可比的。在这里,重要的是要指出,样本大小和老鼠肌肉大小与人类瘦质量的巨大差异可能会影响相关性。我们的工作提供了对啮齿动物握力测试的结构效度的洞察,它显示出与临床握力测试的概念要素的合理重叠。对人类来说,握力是一项高度进化的复杂任务,对中枢神经系统提出了很高的要求最大握力测试要求人脑以空间和时间区分的模式调节手部19块肌肉和前臂另外20块肌肉的招募。因此,在握力测试中测量的力不仅取决于弯曲手指的肌肉的激活,还取决于神经系统参与定向手指以及稳定手和手腕的肌肉的能力。随着年龄的增长,完全激活握力肌肉的神经系统损伤会加剧(回顾,见Clark和Carson26)。神经损伤可能解释了为什么约60%的握力变化可以用人类的肌肉质量来解释。我们推测,在小鼠中,握力和肌肉质量之间的关联性更低是由于类似的神经损伤,但与动物动机相关的更广泛的问题进一步影响了数据除了与肌肉质量的相关性外,在我们的临床前研究中,我们还使用肌肉收缩力作为肌肉功能的非行为性代理测量。 我们之前的研究表明,这些指标是老年小鼠模型中神经肌肉功能的可靠指标。20,27肌肉收缩力与所有五种测试方法都有相关性,进一步支持小鼠握力测试的生理有效性。总之,握力是临床前和临床研究中评估肌肉功能的标准方法。这项工作为临床前衰老研究的技术、研究设计和实施提供了信息。它还提供了洞察在啮齿动物握力测试的结构效度与人类握力测试的概念要素有合理的重叠。我们的研究结果表明,在年轻和老年小鼠之间,全肢法比双侧后肢法在重测可靠性和统计学意义上有轻微的优势。鉴于握力作为老年人整体健康状况指标的临床意义,临床前研究中握力测试技术的优化对未来临床前研究的有效性和可翻译性至关重要,这些研究旨在探索肌肉减少症的机制和对抗与年龄相关的运动功能下降的潜在治疗方法。本工作由NIA/NIH R56AG055795和R03AG067387资助给WDA, R01AG067758资助给WDA和BCC, R01AG044424资助给BCC。作者声明无利益冲突。
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来源期刊
Journal of Cachexia, Sarcopenia and Muscle
Journal of Cachexia, Sarcopenia and Muscle Medicine-Orthopedics and Sports Medicine
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期刊介绍: The Journal of Cachexia, Sarcopenia, and Muscle is a prestigious, peer-reviewed international publication committed to disseminating research and clinical insights pertaining to cachexia, sarcopenia, body composition, and the physiological and pathophysiological alterations occurring throughout the lifespan and in various illnesses across the spectrum of life sciences. This journal serves as a valuable resource for physicians, biochemists, biologists, dieticians, pharmacologists, and students alike.
期刊最新文献
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