Graduate School of Health Sciences, Sapporo Medical University, Sapporo, Japan.
Research Fellow of Japan Society for the Promotion of Science, Tokyo, Japan.
PLoS One. 2019 Oct 9;14(10):e0223551. doi: 10.1371/journal.pone.0223551. eCollection 2019.
Although there is good evidence to indicate a major role of intrinsic impairment of the contractile apparatus in muscle weakness seen in several pathophysiological conditions, the factors responsible for control of myofibrillar function are not fully understood. To investigate the role of mechanical load in myofibrillar function, we compared the skinned fiber force between denervated (DEN) and dexamethasone-treated (DEX) rat skeletal muscles with or without neuromuscular electrical stimulation (ES) training. DEN and DEX were induced by cutting the sciatic nerve and daily injection of dexamethasone (5 mg/kg/day) for 7 days, respectively. For ES training, plantarflexor muscles were electrically stimulated to produce four sets of five isometric contractions each day. In situ maximum torque was markedly depressed in the DEN muscles compared to the DEX muscles (-74% vs. -10%), whereas there was not much difference in the degree of atrophy in gastrocnemius muscles between DEN and DEX groups (-24% vs. -17%). Similar results were obtained in the skinned fiber preparation, with a greater reduction in maximum Ca2+-activated force in the DEN than in the DEX group (-53% vs. -16%). Moreover, there was a parallel decline in myosin heavy chain (MyHC) and actin content per muscle volume in DEN muscles, but not in DEX muscles, which was associated with upregulation of NADPH oxidase (NOX) 2, neuronal nitric oxide synthase (nNOS), and endothelial NOS expression, translocation of nNOS from the membrane to the cytosol, and augmentation of mRNA levels of muscle RING finger protein 1 (MuRF-1) and atrogin-1. Importantly, mechanical load evoked by ES protects against DEN- and DEX-induced myofibrillar dysfunction and these molecular alterations. Our findings provide novel insights regarding the difference in intrinsic contractile properties between DEN and DEX and suggest an important role of mechanical load in preserving myofibrillar function in skeletal muscle.
尽管有充分的证据表明，内在的收缩装置损伤在几种病理生理条件下观察到的肌肉无力中起主要作用，但负责调节肌纤维功能的因素尚未完全了解。为了研究机械负荷在肌纤维功能中的作用，我们比较了去神经（DEN）和地塞米松处理（DEX）大鼠骨骼肌的去神经和地塞米松处理骨骼肌之间的去皮纤维力，这些肌肉有无神经肌肉电刺激（ES）训练。DEN 和 DEX 分别通过切断坐骨神经和每天注射地塞米松（5mg/kg/天）7 天来诱导。对于 ES 训练，通过电刺激跖屈肌每天产生四组 5 次等长收缩。与 DEX 肌肉相比，DEN 肌肉的原位最大扭矩明显降低（-74%比-10%），而 DEN 和 DEX 组之间比目鱼肌的萎缩程度没有太大差异（-24%比-17%）。在去皮纤维制剂中也得到了类似的结果，DEN 组的最大 Ca2+激活力的减少大于 DEX 组（-53%比-16%）。此外，DEN 肌肉中的肌球蛋白重链（MyHC）和肌动蛋白含量与肌肉体积的比例平行下降，但 DEX 肌肉没有，这与 NADPH 氧化酶（NOX）2、神经元型一氧化氮合酶（nNOS）和内皮型一氧化氮合酶表达的上调、nNOS 从膜到细胞质的易位以及肌肉 RING 指蛋白 1（MuRF-1）和 atrogin-1 的 mRNA 水平增加有关。重要的是，ES 引起的机械负荷可防止 DEN 和 DEX 引起的肌纤维功能障碍和这些分子改变。我们的发现为 DEN 和 DEX 之间内在收缩特性的差异提供了新的见解，并表明机械负荷在维持骨骼肌肌纤维功能中的重要作用。
