Spangenburg Espen E, Le Roith Derek, Ward Chris W, Bodine Sue C
Department of Kinesiology, University of Maryland, College Park, MD 21045, USA.
J Physiol. 2008 Jan 1;586(1):283-91. doi: 10.1113/jphysiol.2007.141507. Epub 2007 Nov 1.
Increasing the mechanical load on skeletal muscle results in increased expression of insulin-like growth factor I (IGF-I), which is thought to be a critical step in the induction of muscle hypertrophy. To determine the role of the IGF-I receptor in load-induced skeletal muscle hypertrophy, we utilized a transgenic mouse model (MKR) that expresses a dominant negative IGF-I receptor specifically in skeletal muscle. Skeletal muscle hypertrophy was induced in the plantaris muscle using the functional overload (FO) model, a model which has previously been shown to induce significant elevations of IGF-I expression in skeletal muscle. Adult male wild-type (WT) and MKR mice were subjected to 0, 7 or 35 days of FO. In control or unchallenged animals, the plantaris mass was 11% greater in WT compared to the MKR mice (P < 0.05). After 7 days of FO, plantaris mass increased significantly by 26% and 62% in WT and MKR mice, respectively (P < 0.05). After 35 days of FO, WT and MKR mice demonstrated significant increases of 100% and 122%, respectively, in plantaris mass (P < 0.05). Further, at no time point was the degree of hypertrophy significantly different between the WT and MKR mice. Previous research suggests that IGF-I induces muscle growth through activation of the Akt-mTOR signalling pathway; therefore, we measured the phosphorylation status of Akt and p70(s6k) in the WT and MKR mice after 7 days of FO. Significant increases of approximately 100% and approximately 200% in Akt (Ser-473) and p70(s6k) (Thr-389) phosphorylation were measured in overloaded plantaris from both WT and MKR mice, respectively. Moreover, no differences were detected between the WT and MKR mice. These data suggest that increased mechanical load can induce muscle hypertrophy and activate the Akt and p70(s6k) independent of a functioning IGF-I receptor.
增加骨骼肌的机械负荷会导致胰岛素样生长因子I（IGF-I）表达增加，这被认为是诱导肌肉肥大的关键步骤。为了确定IGF-I受体在负荷诱导的骨骼肌肥大中的作用，我们使用了一种转基因小鼠模型（MKR），该模型在骨骼肌中特异性表达显性负性IGF-I受体。使用功能过载（FO）模型在比目鱼肌中诱导骨骼肌肥大，该模型先前已被证明可诱导骨骼肌中IGF-I表达显著升高。成年雄性野生型（WT）和MKR小鼠接受0、7或35天的FO。在对照或未受挑战的动物中，WT小鼠的比目鱼肌质量比MKR小鼠大11%（P<0.05）。FO 7天后，WT和MKR小鼠的比目鱼肌质量分别显著增加26%和62%（P<0.05）。FO 35天后，WT和MKR小鼠的比目鱼肌质量分别显著增加100%和122%（P<0.05）。此外，在任何时间点，WT和MKR小鼠之间的肥大程度均无显著差异。先前的研究表明，IGF-I通过激活Akt-mTOR信号通路诱导肌肉生长；因此，我们在FO 7天后测量了WT和MKR小鼠中Akt和p70(s6k)的磷酸化状态。在WT和MKR小鼠过载的比目鱼肌中，分别检测到Akt（Ser-473）和p70(s6k)（Thr-389）磷酸化显著增加约100%和约200%。此外，WT和MKR小鼠之间未检测到差异。这些数据表明，增加机械负荷可诱导肌肉肥大并激活Akt和p70(s6k)，而与功能性IGF-I受体无关。
