PDF(Pubmed)
Abstract：
This study was designed to develop an understanding of the pathophysiology of traumatic muscle injury in the context of Western diet (WD; high fat and high sugar) and obesity. The objective was to interrogate the combination of WD and injury on skeletal muscle mass and contractile and metabolic function.
Male and female C57BL/6J mice were randomized into four groups based on a two-factor study design: (1) injury (uninjured vs. volumetric muscle loss [VML]) and (2) diet (WD vs. normal chow [NC]). Electrophysiology was used to test muscle strength and metabolic function in cohorts of uninjured + NC, uninjured + WD, VML + NC and VML + WD at 8 weeks of intervention.
VML-injured male and female mice both exhibited decrements in muscle mass (-17%, P < 0.001) and muscle strength (-28%, P < 0.001); however, VML + WD females had a 28% greater muscle mass compared to VML + NC females (P = 0.034), a compensatory response not detected in males. VML-injured male and female mice both had lower carbohydrate- and fat-supported muscle mitochondrial respiration (JO2 ) and less electron conductance through the electron transport system (ETS); however, male VML-WD had 48% lower carbohydrate-supported JO2 (P = 0.014) and 47% less carbohydrate-supported electron conductance (P = 0.026) compared to male VML + NC, and this diet-injury phenotype was not present in females. ETS electron conductance starts with complex I and complex II dehydrogenase enzymes at the inner mitochondrial membrane, and male VML + WD had 31% less complex I activity (P = 0.004) and 43% less complex II activity (P = 0.005) compared to male VML + NC. This was a diet-injury phenotype not present in females. Pyruvate dehydrogenase (PDH), β-hydroxyacyl-CoA dehydrogenase, citrate synthase, α-ketoglutarate dehydrogenase and malate dehydrogenase metabolic enzyme activities were evaluated as potential drivers of impaired JO2 in the context of diet and injury. There were notable male and female differential effects in the enzyme activity and post-translational regulation of PDH. PDH enzyme activity was 24% less in VML-injured males, independent of diet (P < 0.001), but PDH enzyme activity was not influenced by injury in females. PDH enzyme activity is inhibited by phosphorylation at serine-293 by PDH kinase 4 (PDK4). In males, there was greater total PDH, phospho-PDHser293 and phospho-PDH-to-total PDH ratio in WD mice compared to NC, independent of injury (P ≤ 0.041). In females, PDK4 was 51% greater in WD compared to NC, independent of injury (P = 0.025), and was complemented by greater phospho-PDHser293 (P = 0.001).
Males are more susceptible to muscle metabolic dysfunction in the context of combined WD and traumatic injury compared to females, and this may be due to impaired metabolic enzyme functions.
Male and female C57BL/6J mice were randomized into four groups based on a two-factor study design: (1) injury (uninjured vs. volumetric muscle loss [VML]) and (2) diet (WD vs. normal chow [NC]). Electrophysiology was used to test muscle strength and metabolic function in cohorts of uninjured + NC, uninjured + WD, VML + NC and VML + WD at 8 weeks of intervention.
VML-injured male and female mice both exhibited decrements in muscle mass (-17%, P < 0.001) and muscle strength (-28%, P < 0.001); however, VML + WD females had a 28% greater muscle mass compared to VML + NC females (P = 0.034), a compensatory response not detected in males. VML-injured male and female mice both had lower carbohydrate- and fat-supported muscle mitochondrial respiration (JO2 ) and less electron conductance through the electron transport system (ETS); however, male VML-WD had 48% lower carbohydrate-supported JO2 (P = 0.014) and 47% less carbohydrate-supported electron conductance (P = 0.026) compared to male VML + NC, and this diet-injury phenotype was not present in females. ETS electron conductance starts with complex I and complex II dehydrogenase enzymes at the inner mitochondrial membrane, and male VML + WD had 31% less complex I activity (P = 0.004) and 43% less complex II activity (P = 0.005) compared to male VML + NC. This was a diet-injury phenotype not present in females. Pyruvate dehydrogenase (PDH), β-hydroxyacyl-CoA dehydrogenase, citrate synthase, α-ketoglutarate dehydrogenase and malate dehydrogenase metabolic enzyme activities were evaluated as potential drivers of impaired JO2 in the context of diet and injury. There were notable male and female differential effects in the enzyme activity and post-translational regulation of PDH. PDH enzyme activity was 24% less in VML-injured males, independent of diet (P < 0.001), but PDH enzyme activity was not influenced by injury in females. PDH enzyme activity is inhibited by phosphorylation at serine-293 by PDH kinase 4 (PDK4). In males, there was greater total PDH, phospho-PDHser293 and phospho-PDH-to-total PDH ratio in WD mice compared to NC, independent of injury (P ≤ 0.041). In females, PDK4 was 51% greater in WD compared to NC, independent of injury (P = 0.025), and was complemented by greater phospho-PDHser293 (P = 0.001).
Males are more susceptible to muscle metabolic dysfunction in the context of combined WD and traumatic injury compared to females, and this may be due to impaired metabolic enzyme functions.
摘要：
背景：本研究旨在了解西方饮食（高脂肪和高糖）和肥胖背景下创伤性肌肉损伤的病理生理学。目的是询问WD和损伤对骨骼肌质量以及收缩和代谢功能的组合。
方法：根据双因素研究设计，将雄性和雌性C57BL/6J小鼠随机分为四组：（1）损伤（未损伤vs.体积肌肉损失[VML])和(2)饮食(WDvs.正常食物[NC])。电生理学用于测试未受伤的NC队列中的肌肉力量和代谢功能，未受伤+WD,干预8周时VML+NC和VML+WD。
结果：VML损伤的雄性和雌性小鼠的肌肉质量均下降（-17％，P<0.001）和肌肉力量（-28％，P<0.001)；然而，与VML+NC女性相比，VML+WD女性的肌肉质量增加了28％（P=0.034），在男性中未检测到的代偿反应。VML损伤的雄性和雌性小鼠的碳水化合物和脂肪支持的肌肉线粒体呼吸（JO2）均较低，并且通过电子传输系统（ETS）的电子传导较低；但是，男性VML-WD与男性VML+NC相比，碳水化合物支持的JO2低48%(P=0.014)，碳水化合物支持的电子电导低47%(P=0.026)，这种饮食损伤表型在女性中不存在。ETS电子传导从线粒体内膜的复合物I和复合物II脱氢酶开始，与男性VMLNC相比，男性VMLWD的复合I活性降低了31％（P=0.004），复合II活性降低了43％（P=0.005）。这是女性中不存在的饮食损伤表型。丙酮酸脱氢酶(PDH),β-羟酰基辅酶A脱氢酶，柠檬酸合成酶，在饮食和损伤的情况下，α-酮戊二酸脱氢酶和苹果酸脱氢酶代谢酶活性被评估为JO2受损的潜在驱动因素。在PDH的酶活性和翻译后调节中存在明显的男性和女性差异效应。在VML损伤的男性中，PDH酶活性降低了24%，独立于饮食（P<0.001），但是PDH酶活性不受女性伤害的影响。PDH酶活性被PDH激酶4(PDK4)在丝氨酸-293处的磷酸化所抑制。在男性中，总PDH更大，与NC相比，WD小鼠中的磷酸-PDHser293和磷酸-PDH与总PDH的比率，与损伤无关(P≤0.041)。在女性中，与NC相比，WD中的PDK4高出51%，与损伤无关（P=0.025），并补充了更多的磷酸-PDHser293（P=0.001）。
结论：与女性相比，男性在合并WD和创伤性损伤的情况下更容易发生肌肉代谢功能障碍，这可能是由于代谢酶功能受损。
方法：根据双因素研究设计，将雄性和雌性C57BL/6J小鼠随机分为四组：（1）损伤（未损伤vs.体积肌肉损失[VML])和(2)饮食(WDvs.正常食物[NC])。电生理学用于测试未受伤的NC队列中的肌肉力量和代谢功能，未受伤+WD,干预8周时VML+NC和VML+WD。
结果：VML损伤的雄性和雌性小鼠的肌肉质量均下降（-17％，P<0.001）和肌肉力量（-28％，P<0.001)；然而，与VML+NC女性相比，VML+WD女性的肌肉质量增加了28％（P=0.034），在男性中未检测到的代偿反应。VML损伤的雄性和雌性小鼠的碳水化合物和脂肪支持的肌肉线粒体呼吸（JO2）均较低，并且通过电子传输系统（ETS）的电子传导较低；但是，男性VML-WD与男性VML+NC相比，碳水化合物支持的JO2低48%(P=0.014)，碳水化合物支持的电子电导低47%(P=0.026)，这种饮食损伤表型在女性中不存在。ETS电子传导从线粒体内膜的复合物I和复合物II脱氢酶开始，与男性VMLNC相比，男性VMLWD的复合I活性降低了31％（P=0.004），复合II活性降低了43％（P=0.005）。这是女性中不存在的饮食损伤表型。丙酮酸脱氢酶(PDH),β-羟酰基辅酶A脱氢酶，柠檬酸合成酶，在饮食和损伤的情况下，α-酮戊二酸脱氢酶和苹果酸脱氢酶代谢酶活性被评估为JO2受损的潜在驱动因素。在PDH的酶活性和翻译后调节中存在明显的男性和女性差异效应。在VML损伤的男性中，PDH酶活性降低了24%，独立于饮食（P<0.001），但是PDH酶活性不受女性伤害的影响。PDH酶活性被PDH激酶4(PDK4)在丝氨酸-293处的磷酸化所抑制。在男性中，总PDH更大，与NC相比，WD小鼠中的磷酸-PDHser293和磷酸-PDH与总PDH的比率，与损伤无关(P≤0.041)。在女性中，与NC相比，WD中的PDK4高出51%，与损伤无关（P=0.025），并补充了更多的磷酸-PDHser293（P=0.001）。
结论：与女性相比，男性在合并WD和创伤性损伤的情况下更容易发生肌肉代谢功能障碍，这可能是由于代谢酶功能受损。
