Resistance training recovers attenuated APPL1 expression and improves insulin-induced Akt signal activation in skeletal muscle of type 2 diabetic rats.

Adapter protein containing Pleckstrin homology (PH) domain, phosphotyrosine-binding (PTB) domain, and leucine zipper motif 1 (APPL1) has been reported as a positive regulator of insulin-stimulated Akt activation. The expression of APPL1 is reduced in skeletal muscles of type 2 diabetic (T2D) animals, implying that APPL1 may be an important factor affecting insulin sensitivity. However, the regulation of APPL1 expression and the physiological interventions modulating these effects are unclear. Accordingly, we first confirmed that APPL1 expression and insulin-induced Akt phosphorylation were significantly attenuated in skeletal muscles of T2D rats. Additionally, we found that APPL1 expression levels were significantly correlated with fasting blood glucose levels. Next, we identified important signals involved in the expression of APPL1. APPL1 mRNA expression increased upon AMP-activated protein kinase, calcium, p38 mitogen-activated protein kinase, and insulin-like growth factor-1 signal activation. Moreover, acute resistance exercise in vivo significantly activated these signaling pathways. Finally, through in vivo experiments, we found that chronic resistance training (RT) increased APPL1 expression and activated insulin-induced Akt signaling in skeletal muscles of rats with T2D. Furthermore, variations in APPL1 expression (i.e., the difference between control and RT muscles) significantly correlated with variations in insulin-stimulated Akt phosphorylation under the same conditions. Therefore, chronic RT recovered attenuated APPL1 expression and improved insulin-stimulated Akt phosphorylation in skeletal muscles of T2D rats. Accordingly, APPL1 may be a key regulator of insulin resistance in skeletal muscle, and RT may be an important physiological treatment increasing APPL1 expression, which is attenuated in T2D.