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

Abstract

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.

The effects of resistance training on bone mineral density and bone quality in type 2 diabetic rats

“…Furthermore, RT used in this study has been reported to increase IGF‐1 protein expression, and improve glucose metabolism in muscle (Kido et al. ), which might indirectly enhance bone metabolism. From the above, we considered that RT has direct and indirect beneficial effects on improving BMD and bone structure in both cortical and trabecular bone of OLETF as well as LETO rats.…”

“…; Kido et al. ). Briefly, under isoflurane anesthesia, the whole right gastrocnemius muscle (RT leg) was subjected to maximal isometric contraction by percutaneous electrical stimulation (5 sets of 3‐sec stimulations × 10 contractions/set with a 7‐sec interval between contractions and a 3‐min rest between sets) with an electric stimulator and isolator (SS‐104J; Nihon Kohden, Tokyo, Japan).…”

“…; Kido et al. ). Analysis was performed between four and seven samples, because of technical variations of sample preparations.…”

“…IPGTT was performed as described previously (Kido et al. ). Briefly, after overnight fasting and under isoflurane anesthesia, glucose (2 g/kg) was injected intraperitoneally, and whole blood glucose was monitored for 2 h. Blood samples were collected from the tail vein, and glucose levels were measured with a glucose meter (Breeze 2; Bayer, Leverkusen, Germany).…”

“…) than other representative methods, and it has been reported that resistance training using electrical stimulation could improve intramuscular glucose metabolism (Kido et al. , ). Therefore, we hypothesized that resistance training has beneficial effects on bone quality, which is reduced by T2DM.…”