受损肌肉自行再生的机制

2021/3/19 11:24:46 本站原创 佚名 【字体:

编译   廖联明

骨骼肌是由一束束收缩的肌纤维组成的,每一根肌纤维都被卫星细胞包围着,这些肌肉干细胞可以产生新的肌肉纤维。多亏了这些卫星细胞的工作,即使在剧烈运动中受到损伤或撕裂,肌肉纤维也可以再生。卫星细胞在肌肉发育阶段的肌肉生长和力量训练期间的肌肉增粗过程中也起着重要作用。然而,在像肌营养不良和年龄相关性肌萎缩(肌萎缩症)等难治性肌病中,卫星细胞的数量和功能下降。因此,了解卫星细胞在肌肉再生治疗中的调节机制是非常重要的。

在成熟骨骼肌中,卫星细胞通常处于休眠状态。一旦肌肉损伤后,卫星细胞被迅速激活并反复增殖。在随后的肌细胞生成过程中,它们通过与现有肌纤维融合或与之融合来分化和再生肌纤维。在这三个步骤(卫星细胞激活、增殖和肌肉分化)中,对第一步激活是如何诱导的知之甚少。

由于卫星细胞在肌肉纤维受损时会被激活,研究人员假设肌肉损伤本身可能会触发激活。然而,这一点很难在肌肉损伤的动物模型中得到证实,因此他们构建了一个细胞培养模型,其中从小鼠肌肉组织中分离出来的单个肌肉纤维受到物理损伤和破坏。利用这个损伤模型,他们发现从受伤的肌肉纤维中泄漏的成分激活了卫星细胞,激活的细胞进入了细胞分裂的G1准备期。此外,当被破坏的组分被移除时,被激活的细胞恢复到休眠状态,从而表明受损组分起到激活开关的作用。

研究小组将泄漏的成分命名为受损肌纤维衍生因子DMDFs),以断裂的肌肉纤维命名,并用质谱法对其进行鉴定。大多数被鉴定的蛋白质是代谢酶,包括糖酵解酶,如GAPDH,和肌肉衍生酶,它们被用作肌肉异常和疾病的生物标志物。GAPDH被称为月光蛋白,除了在糖酵解中的原始功能外,它还有其他作用,例如细胞死亡控制和免疫反应调节。因此,研究人员分析了包括GAPDH在内的受损肌纤维衍生因子对卫星细胞激活的影响,并证实了暴露导致其进入G1期。此外,研究人员将GAPDH注射到小鼠骨骼肌中,观察到随后药物诱导的肌肉损伤后卫星细胞加速增殖。这些结果表明,受损肌纤维衍生因子具有激活休眠卫星细胞和诱导损伤后快速肌肉再生的能力。断裂肌肉激活卫星细胞的机制是一种高效的组织再生机制。

然而,受损肌纤维衍生因子如何激活卫星细胞的详细分子机制仍然是未来研究的一个不清楚的问题。除了卫星细胞激活外,受损肌纤维衍生因子的月光功能也将多样化。最近的研究表明,骨骼肌分泌各种影响其他器官和组织的因素,如大脑和脂肪进入血液,因此受损肌纤维衍生因子可能通过血液循环参与受伤肌肉与其他器官之间的联系。进一步阐明受损肌纤维衍生因子的功能可以阐明某些肌肉疾病的病理学,并有助于新药的开发。

 

——原文

Damaged muscles regenerate themselves

 

Skeletal muscle is made up of bundles of contracting muscle fibers and each muscle fiber is surrounded by satellite cells -- muscle stem cells that can produce new muscle fibers. Thanks to the work of these satellite cells, muscle fibers can be regenerated even after being bruised or torn during intense exercise. Satellite cells also play essential roles in muscle growth during developmental stages and muscle hypertrophy during strength training. However, in refractory muscle diseases like muscular dystrophy and age-related muscular fragility (sarcopenia), the number and function of satellite cells decreases. It is therefore important to understand the regulatory mechanism of satellite cells in muscle regeneration therapy.

 

In mature skeletal muscle, satellite cells are usually present in a dormant state. Upon stimulation after muscle injury, satellite cells are rapidly activated and proliferate repeatedly. During the subsequent myogenesis, they differentiate and regenerate muscle fibers by fusing with existing muscle fibers or with together. Of these three steps (satellite cell activation, proliferation, and muscle differentiation), little is known about how the first step, activation, is induced.

 

Since satellite cells are activated when muscle fibers are damaged, researchers hypothesized that muscle damage itself could trigger activation. However, this is difficult to prove in animal models of muscle injury so they constructed a cell culture model in which single muscle fibers, isolated from mouse muscle tissue, were physically damaged and destroyed. Using this injury model, they found that components leaking from the injured muscle fibers activated satellite cells, and the activated cells entered the G1 preparatory phase of cell division. Further, the activated cells returned to a dormant state when the damaged components were removed, thereby suggesting that the damaged components act as the activation switch.

 

The research team named the leaking components "Damaged myofiber-derived factors" (DMDFs), after the broken muscle fibers, and identified them using mass spectrometry. Most of the identified proteins were metabolic enzymes, including glycolytic enzymes such as GAPDH, and muscle deviation enzymes that are used as biomarkers for muscle disorders and diseases. GAPDH is known as a "moonlighting protein" that has other roles in addition to its original function in glycolysis, such as cell death control and immune response mediation. The researchers therefore analyzed the effects of DMDFs, including GAPDH, on satellite cell activation and confirmed that exposure resulted in their entry into the G1 phase. Furthermore, the researchers injected GAPDH into mouse skeletal muscle and observed accelerated satellite cell proliferation after subsequent drug-induced muscle damage. These results suggest that DMDFs have the ability to activate dormant satellite cells and induce rapid muscle regeneration after injury. The mechanism by which broken muscle activates satellite cells is a highly effective and efficient tissue regeneration mechanism.

However, the detailed molecular mechanism of how DMDFs activate satellite cells remains an unclear issue for future research. In addition to satellite cell activation, DMDF moonlighting functions are expected to be diverse. Recent studies have shown that skeletal muscle secretes various factors that affect other organs and tissues, such as the brain and fat, into the bloodstream, so it may be possible that DMDFs are involved in the linkage between injured muscle and other organs via blood circulation. Further elucidation of the functions of DMDFs could clarify the pathologies of some muscle diseases and help in the development of new drugs.

 

Journal Reference:

Yoshifumi Tsuchiya, Yasuo Kitajima, Hiroshi Masumoto, Yusuke Ono. Damaged Myofiber-Derived Metabolic Enzymes Act as Activators of Muscle Satellite Cells. Stem Cell Reports, 2020; DOI: 10.1016/j.stemcr.2020.08.002

 

 

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