Adeno-associated virus-mediated expression of an inactive CaMKIIβ mutant enhances muscle mass and strength in mice
Adeno-associated virus-mediated expression of an inactive CaMKIIβ mutant enhances muscle mass and strength in mice
复制标题
腺相关病毒介导的失活 CaMKIIβ 突变体表达可增强小鼠的肌肉质量和力量
DOI：
10.1016/j.bbrc.2021.12.027
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发表时间：
2022
影响因子：
3.1
通讯作者：
Yamanashi Yuji
中科院分区：
文献类型：
--
作者：
Eguchi Takahiro;Yamanashi Yuji
肌肉质量和力量的同时减少经常在许多情况下被观察到，包括神经肌肉疾病，衰老，以及由于肢体静止或长时间卧床而导致的肌肉不活动。因此，确定控制骨骼肌质量和力量的分子机制对于开发旨在对抗肌肉损失(肌肉萎缩)的干预措施是至关重要的。最近有报道称，运动神经失神经损伤所致的肌肉萎缩与肌肉中钙/钙调素依赖性蛋白丝氨酸/苏氨酸激酶IIβ(CaMKIIβ)的表达增加有关。此外，抑制CaMKII家族激酶的KN-93磷酸治疗，部分抑制了失神经诱导的肌肉萎缩。因此，为了测试CaMKIIβ在肌肉质量调节中的可能作用，我们构建了编码野生型(AAV-WT)、失活(AAV-K43M)和结构性活性(AAV-T287D)CaMKIIβ的重组腺相关病毒载体，并在3月龄时将其注射到小鼠左后肢胫骨前肌中。虽然AAv-WT感染诱导了外源性CaMKIIβ在后肢肌肉中的表达，但肌肉质量和力量没有明显变化。相比之下，AAV-K43-M和AAV-T287D感染分别诱导相应突变体的外源表达，并分别显著增加或降低感染后肢的肌肉质量和力量。总之，这些发现证明了CaMKIIβ作为增强肌肉质量和力量的新治疗靶点的潜力。
A concurrent reduction in muscle mass and strength is frequently observed in numerous conditions, including neuromuscular disease, ageing, and muscle inactivity due to limb immobilization or prolonged bed rest. Thus, identifying the molecular mechanisms that control skeletal muscle mass and strength is fundamental for developing interventions aimed at counteracting muscle loss (muscle atrophy). It was recently reported that muscle atrophy induced by denervation of motor nerves was associated with increased expression of Ca2+/calmodulin-dependent protein serine/threonine kinase II β (CaMKIIβ) in muscle. In addition, treatment with KN-93 phosphate, which inhibits CaMKII-family kinases, partly suppressed denervation-induced muscle atrophy. Therefore, to test a possible role for CaMKIIβ in muscle mass regulation, we generated and injected recombinant adeno-associated virus (AAV) vectors encoding wild-type (AAV-WT), inactive (AAV-K43 M), or constitutively active (AAV-T287D) CaMKIIβ into the left hindlimb tibialis anterior muscle of mice at three months of age. Although AAV-WT infection induced expression of exogenous CaMKIIβ in the hindlimb muscle, no significant changes in muscle mass and strength were observed. By contrast, AAV-K43 M or AAV-T287D infection induced exogenous expression of the corresponding mutants and significantly increased or decreased the muscle mass and strength of the infected hind limb, respectively. Together, these findings demonstrate the potential of CaMKIIβ as a novel therapeutic target for enhancing muscle mass and strength.