Venetian Institute of Molecular Medicine, Padova, Italy.
Minderbroedersberg, Maastricht, LK, The Netherlands.
J Cachexia Sarcopenia Muscle. 2019 Jun;10(3):630-642. doi: 10.1002/jcsm.12409. Epub 2019 Mar 20.
Skeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle-secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle-derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet.
Muscle-specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21-dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy.
We show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting-induced muscle atrophy and weakness. The mass of isolated muscles from control-fasted mice was reduced by 15-25% (P < 0.05) compared with fed control mice. FGF21-null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control-fasted muscles (P < 0.01), together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% (P < 0.05). Bnip3 inhibition protected against FGF21-dependent muscle wasting in adult animals (P < 0.05).
FGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.
骨骼肌是一种具有可塑性的组织，通过分泌肌肉因子和肌代谢物来适应运动、营养和应激的变化。这些肌肉分泌的因子具有自分泌、旁分泌和内分泌作用，有助于维持全身的稳态。衰老性肌少症、癌症恶病质和糖尿病中的肌肉功能障碍与全身生理稳态的破坏密切相关。在正常健康的肌肉中，肌肉因子成纤维细胞生长因子 21（FGF21）的表达水平非常低。然而，禁食、内质网应激、线粒体肌病和代谢紊乱会导致其从肌肉中释放。尽管我们对肌肉来源的 FGF21 的全身作用的理解呈指数增长，但 FGF21 对肌肉功能的直接贡献尚未得到研究。
为了研究 FGF21 缺失对骨骼肌质量和力量的影响，生成了肌肉特异性 FGF21 敲除小鼠。为了确定饥饿状态下肌肉衍生的 FGF21 依赖性适应的机制，该研究在喂食和禁食的成年小鼠的肌肉中进行。在骨骼肌中过表达 FGF21 以评估 FGF21 是否足以自身诱导肌肉萎缩。
我们发现，在纤维类型分布、纤维大小和肌肉力量方面，FGF21 本身在基础条件下对肌肉稳态没有贡献。相比之下，FGF21 是饥饿诱导的肌肉萎缩和虚弱所必需的。与喂食对照组相比，对照组禁食小鼠的分离肌肉质量减少了 15-25%（P<0.05）。然而，FGF21 敲除肌肉在禁食期间明显免受肌肉损失和虚弱的影响。这种重要的保护作用归因于与对照组禁食肌肉相比，FGF21 敲除肌肉在禁食期间蛋白质合成率的维持（P<0.01），以及通过调节线粒体蛋白 Bnip3 显著减少线粒体自噬通量。通过在肌肉中过表达 FGF21 来支持 FGF21 对萎缩程序的贡献，这足以诱导自噬并使肌肉损失 15%（P<0.05）。Bnip3 抑制可防止 FGF21 依赖性肌肉消耗（P<0.05）。
FGF21 是调节肌肉质量的新因子，需要自噬蛋白 Bnip3。
