Integrative Muscle Biology Laboratory, University of South Carolina , Columbia, South Carolina.
Center for Colon Cancer Research, University of South Carolina , Columbia, South Carolina.
J Appl Physiol (1985). 2018 Mar 1;124(3):684-695. doi: 10.1152/japplphysiol.00897.2017. Epub 2017 Nov 9.
While cancer-induced skeletal muscle wasting has been widely investigated, the drivers of cancer-induced muscle functional decrements are only beginning to be understood. Decreased muscle function impacts cancer patient quality of life and health status, and several potential therapeutics have failed in clinical trials due to a lack of functional improvement. Furthermore, systemic inflammation and intrinsic inflammatory signaling's role in the cachectic disruption of muscle function requires further investigation. We examined skeletal muscle functional properties during cancer cachexia and determined their relationship to systemic and intrinsic cachexia indices. Male Apc (MIN) mice were stratified by percent body weight loss into weight stable (WS; <5% loss) or cachectic (CX; >5% loss). Age-matched C57BL/6 littermates served as controls. Tibialis anterior (TA) twitch properties, tetanic force, and fatigability were examined in situ. TA protein and mRNA expression were examined in the nonstimulated leg. CX decreased muscle mass, tetanic force (P), and specific tetanic force (P). Whole body and muscle fatigability were increased in WS and CX. CX had slower contraction rates, +dP/d t and -dP/d t, which were inversely associated with muscle signal transducer and activator of transcription 3 ( STAT3) and p65 activation. STAT3 and p65 activation were also inversely associated with P. However, STAT3 was not related to P or fatigue. Muscle suppressor of cytokine signaling 3 mRNA expression was negatively associated with TA weight, P, and P but not fatigue. Our study demonstrates that multiple functional deficits that occur with cancer cachexia are associated with increased muscle inflammatory signaling. Notably, muscle fatigability is increased in the MIN mouse before cachexia development. NEW & NOTEWORTHY Recent studies have identified decrements in skeletal muscle function during cachexia. We have extended these studies by directly relating decrements in muscle function to established cachexia indices. Our results demonstrate that a slow-fatigable contractile phenotype is developed during the progression of cachexia that coincides with increased muscle inflammatory signaling. Furthermore, regression analysis identified predictors of cancer-induced muscle dysfunction. Last, we report the novel finding that whole body and muscle fatigability were increased before cachexia development.
虽然癌症引起的骨骼肌消耗已经得到了广泛的研究，但癌症引起的肌肉功能下降的驱动因素才刚刚开始被理解。肌肉功能下降会影响癌症患者的生活质量和健康状况，并且由于缺乏功能改善，几种潜在的治疗方法在临床试验中都失败了。此外，全身炎症和内在炎症信号在消耗性肌肉功能障碍中的作用需要进一步研究。我们在癌症恶病质期间检查了骨骼肌的功能特性，并确定了它们与全身和内在恶病质指标的关系。雄性 Apc（MIN）小鼠按体重百分比损失分为体重稳定（WS；<5%损失）或恶病质（CX；>5%损失）。年龄匹配的 C57BL/6 同窝仔作为对照。在原位检查比目鱼肌（TA）的抽搐特性、强直力和疲劳性。在未刺激的腿部检查 TA 蛋白和 mRNA 的表达。WS 和 CX 中，肌肉质量、强直力（P）和特定强直力（P）降低。全身和肌肉疲劳性在 WS 和 CX 中增加。CX 收缩速度较慢，+dP/d t 和-dP/d t，与肌肉信号转导和转录激活因子 3（STAT3）和 p65 激活呈负相关。STAT3 和 p65 激活也与 P 呈负相关。然而，STAT3 与 P 或疲劳无关。肌肉细胞因子信号转导抑制因子 3 mRNA 的表达与 TA 重量、P 和 P 呈负相关，但与疲劳无关。我们的研究表明，与癌症恶病质相关的多种功能缺陷与肌肉炎症信号的增加有关。值得注意的是，在恶病质发展之前，MIN 小鼠的肌肉疲劳性就增加了。新的和值得注意的是，最近的研究已经确定了恶病质期间骨骼肌功能的下降。我们通过将肌肉功能的下降与既定的恶病质指标直接相关，扩展了这些研究。我们的结果表明，在恶病质进展过程中，出现了一种缓慢疲劳的收缩表型，这与肌肉炎症信号的增加相一致。此外，回归分析确定了癌症引起的肌肉功能障碍的预测因子。最后，我们报告了一个新的发现，即全身和肌肉疲劳性在恶病质发生之前就已经增加了。
