Department of Physiology and Pharmacology, University of Georgia, Athens, GA, USA.
Regenerative Bioscience Center, University of Georgia, Athens, GA, USA.
J Cachexia Sarcopenia Muscle. 2023 Dec;14(6):2835-2850. doi: 10.1002/jcsm.13361. Epub 2023 Oct 25.
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 (JO ) and less electron conductance through the electron transport system (ETS); however, male VML-WD had 48% lower carbohydrate-supported JO (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 JO 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-PDH 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-PDH (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.
本研究旨在探讨西式饮食（高脂肪、高糖）和肥胖对创伤性肌肉损伤的病理生理学的影响。目的是研究 WD 和损伤对骨骼肌质量以及收缩和代谢功能的联合作用。
根据两因素研究设计，将雄性和雌性 C57BL/6J 小鼠随机分为四组：（1）损伤（未损伤与容量损失[VML]）和（2）饮食（WD 与正常饮食[NC]）。在干预 8 周后，用电生理学方法测试未损伤+NC、未损伤+WD、VML+NC 和 VML+WD 这四组的肌肉力量和代谢功能。
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，VML+WD 的雌性小鼠的肌肉质量比 VML+NC 的雌性小鼠增加了 28%（P=0.034），这种代偿反应在雄性小鼠中没有发现。VML 损伤的雄性和雌性小鼠的肌肉线粒体呼吸（JO）均受碳水化合物和脂肪支持，电子传递系统（ETS）的电子传导能力也较低；然而，雄性 VML-WD 的碳水化合物支持的 JO 降低了 48%（P=0.014），碳水化合物支持的电子传导能力降低了 47%（P=0.026），与雄性 VML+NC 相比，而这种饮食损伤表型在雌性小鼠中不存在。ETS 电子传导始于线粒体膜内的复合体 I 和 II 脱氢酶，雄性 VML+WD 的复合体 I 活性降低了 31%（P=0.004），复合体 II 活性降低了 43%（P=0.005），与雄性 VML+NC 相比。这是一种在雌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、柠檬酸合酶、α-酮戊二酸脱氢酶和苹果酸脱氢酶代谢酶活性被评估为饮食和损伤影响下 JO 受损的潜在驱动因素。在 PDH 的酶活性和翻译后调节方面，存在明显的雄性和雌性差异效应。VML 损伤的雄性小鼠的 PDH 酶活性降低了 24%，与饮食无关（P<0.001），但在雌性小鼠中，损伤对 PDH 酶活性没有影响。PDH 酶活性通过 PDH 激酶 4（PDK4）在丝氨酸-293 上的磷酸化而受到抑制。在雄性小鼠中，与 NC 相比，WD 组的总 PDH、磷酸化 PDH 和磷酸化 PDH 与总 PDH 的比值更高，与损伤无关（P≤0.041）。在雌性小鼠中，与 NC 相比，PDK4 增加了 51%，与损伤无关（P=0.025），并伴有磷酸化 PDH 增加（P=0.001）。
与雌性相比，雄性在 WD 和创伤性损伤的联合作用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所致。
