INRAE, Unité de Nutrition Humaine (UNH), Université Clermont Auvergne, Clermont-Ferrand, France.
Institute of Biomolecular Chemistry, National Research Council, Pozzuoli, Italy.
J Cachexia Sarcopenia Muscle. 2022 Feb;13(1):662-676. doi: 10.1002/jcsm.12855. Epub 2021 Dec 2.
Activation of the endocannabinoid system (ECS) is associated with the development of obesity and insulin resistance, and with perturbed skeletal muscle development. Age-related sarcopenia is a progressive and generalized skeletal muscle disorder involving an accelerated loss of muscle mass and function, with changes in skeletal muscle protein homeostasis due to lipid accumulation and anabolic resistance. Hence, both obesity and sarcopenia share a common set of pathophysiological alterations leading to skeletal muscle impairment. The aim of this study was to characterize how sarcopenia impacts the ECS and if these modifications were related to the loss of muscle mass and function associated with aging in rats.
Six-month-old and 24-month-old male rats were used to measure the contractile properties of the plantarflexors (isometric torque-frequency relationship & concentric power-velocity relationship) and to evaluate locomotor activity, motor coordination, and voluntary gait by open field, rotarod, and catwalk tests, respectively. Levels of endocannabinoids (AEA & 2-AG) and endocannabinoid-like molecules (OEA & PEA) were measured by LCF-MS/MS in plasma, skeletal muscle, and adipose tissue, while the expression of genes coding for the ECS were investigated by quantitative reverse transcription PCR (RT-qPCR).
Sarcopenia in old rats was exemplified by a 49% decrease in hindlimb muscle mass (P < 0.01), which was associated with severe impairment of isometric torque, power, voluntary locomotor activity, motor coordination, and gait quality. Sarcopenia was associated with (1) increased 2-AG (+32%, P = 0.07) and reduced PEA and OEA levels in the plasma (-25% and -40%, respectively, P < 0.01); (2) an increased content of AEA, PEA, and OEA in subcutaneous adipose tissue (P < 0.01); and (3) a four-fold increase of 2-AG content in the soleus (P < 0.01) and a reduced OEA content in EDL (-80%, P < 0.01). These alterations were associated with profound modifications in the expression of the ECS genes in the adipose tissue and skeletal muscle.
Taken together, these findings demonstrate that circulating and peripheral tissue endocannabinoid tone are altered in sarcopenia. They also demonstrate that OEA plasma levels are associated with skeletal muscle function and loss of locomotor activity in rats, suggesting OEA could be used as a circulating biomarker for sarcopenia.
内源性大麻素系统 (ECS) 的激活与肥胖和胰岛素抵抗的发展以及骨骼肌发育紊乱有关。与年龄相关的肌肉减少症是一种进行性和全身性的骨骼肌疾病，涉及肌肉质量和功能的加速丧失，由于脂质积累和合成代谢抵抗导致骨骼肌蛋白动态平衡发生变化。因此，肥胖和肌肉减少症都有一组共同的导致骨骼肌损伤的病理生理改变。本研究的目的是描述肌肉减少症如何影响 ECS，如果这些改变与大鼠衰老相关的肌肉质量和功能丧失有关。
使用 6 个月大和 24 个月大的雄性大鼠测量跖屈肌的收缩特性（等长扭矩-频率关系和向心功率-速度关系），并通过开放式场地、旋转棒和猫道试验分别评估运动活动、运动协调和自愿步态。通过 LCF-MS/MS 测量血浆、骨骼肌和脂肪组织中的内源性大麻素（AEA 和 2-AG）和内源性大麻素样分子（OEA 和 PEA）水平，同时通过定量逆转录 PCR (RT-qPCR) 研究编码 ECS 的基因的表达。
老年大鼠的肌肉减少症表现为后肢肌肉质量减少 49%（P<0.01），这与等长扭矩、功率、自愿运动活动、运动协调和步态质量严重受损有关。肌肉减少症与（1）血浆中 2-AG 增加（+32%，P=0.07）和 PEA 和 OEA 水平降低（分别降低 25%和 40%，P<0.01）；（2）皮下脂肪组织中 AEA、PEA 和 OEA 含量增加（P<0.01）；（3）比目鱼肌中 2-AG 含量增加四倍（P<0.01）和 EDL 中 OEA 含量减少 80%（P<0.01）。这些改变与脂肪组织和骨骼肌中 ECS 基因表达的深刻改变有关。
综上所述，这些发现表明，循环和外周组织内源性大麻素的张力在肌肉减少症中发生改变。它们还表明，PEA 血浆水平与大鼠骨骼肌功能和运动活动丧失有关，提示 OEA 可作为肌肉减少症的循环生物标志物。
