Camerino Giulia Maria, Desaphy Jean-François, De Bellis Michela, Capogrosso Roberta Francesca, Cozzoli Anna, Dinardo Maria Maddalena, Caloiero Roberta, Musaraj Kejla, Fonzino Adriano, Conte Elena, Jagerschmidt Catherine, Namour Florence, Liantonio Antonella, De Luca Annamaria, Conte Camerino Diana, Pierno Sabata
Section of Pharmacology, Dept. of Pharmacy & Drug Sciences, University of Bari "Aldo Moro", Bari, Italy.
Galapagos-SASU, Romainville, France.
PLoS One. 2015 Jun 11;10(6):e0129686. doi: 10.1371/journal.pone.0129686. eCollection 2015.
Muscle disuse produces severe atrophy and a slow-to-fast phenotype transition in the postural Soleus (Sol) muscle of rodents. Antioxidants, amino-acids and growth factors were ineffective to ameliorate muscle atrophy. Here we evaluate the effects of nandrolone (ND), an anabolic steroid, on mouse skeletal muscle atrophy induced by hindlimb unloading (HU). Mice were pre-treated for 2-weeks before HU and during the 2-weeks of HU. Muscle weight and total protein content were reduced in HU mice and a restoration of these parameters was found in ND-treated HU mice. The analysis of gene expression by real-time PCR demonstrates an increase of MuRF-1 during HU but minor involvement of other catabolic pathways. However, ND did not affect MuRF-1 expression. The evaluation of anabolic pathways showed no change in mTOR and eIF2-kinase mRNA expression, but the protein expression of the eukaryotic initiation factor eIF2 was reduced during HU and restored by ND. Moreover we found an involvement of regenerative pathways, since the increase of MyoD observed after HU suggests the promotion of myogenic stem cell differentiation in response to atrophy. At the same time, Notch-1 expression was down-regulated. Interestingly, the ND treatment prevented changes in MyoD and Notch-1 expression. On the contrary, there was no evidence for an effect of ND on the change of muscle phenotype induced by HU, since no effect of treatment was observed on the resting gCl, restCa and contractile properties in Sol muscle. Accordingly, PGC1α and myosin heavy chain expression, indexes of the phenotype transition, were not restored in ND-treated HU mice. We hypothesize that ND is unable to directly affect the phenotype transition when the specialized motor unit firing pattern of stimulation is lacking. Nevertheless, through stimulation of protein synthesis, ND preserves protein content and muscle weight, which may result advantageous to the affected skeletal muscle for functional recovery.
肌肉废用会导致啮齿动物比目鱼肌（Sol）出现严重萎缩以及从慢肌表型向快肌表型转变。抗氧化剂、氨基酸和生长因子对改善肌肉萎缩无效。在此，我们评估合成代谢类固醇诺龙（ND）对后肢卸载（HU）诱导的小鼠骨骼肌萎缩的影响。小鼠在HU前2周及HU的2周期间接受预处理。HU小鼠的肌肉重量和总蛋白含量降低，而在接受ND治疗的HU小鼠中这些参数得以恢复。通过实时PCR分析基因表达表明，HU期间MuRF-1增加，但其他分解代谢途径的参与程度较小。然而，ND并未影响MuRF-1的表达。对合成代谢途径的评估显示，mTOR和eIF2激酶的mRNA表达没有变化，但真核起始因子eIF2的蛋白表达在HU期间降低，并通过ND得以恢复。此外，我们发现再生途径参与其中，因为HU后观察到的MyoD增加表明，萎缩会促使肌源性干细胞分化。同时，Notch-1表达下调。有趣的是，ND治疗可防止MyoD和Notch-1表达发生变化。相反，没有证据表明ND对HU诱导的肌肉表型变化有影响，因为在Sol肌中未观察到治疗对静息gCl、静息Ca和收缩特性有影响。因此，在接受ND治疗的HU小鼠中，作为表型转变指标的PGC1α和肌球蛋白重链表达并未恢复。我们推测，当缺乏专门的运动单位放电模式刺激时，ND无法直接影响表型转变。尽管如此，通过刺激蛋白质合成，ND可维持蛋白质含量和肌肉重量，这可能有利于受影响的骨骼肌功能恢复。
