Beneficial effects of melatonin on stroke-induced muscle atrophy in focal cerebral ischemic rats

Abstract

MUSCLE ATROPHY IS THE RESULT OF TWO OPPOSING CONDITIONS THAT CAN BE FOUND IN PATHOLOGICAL OR DISEASED MUSCLES: an imbalance in protein synthesis and degradation mechanisms. Thus, we investigated whether exogenous melatonin could regulate muscle components in stroke-induced muscle atrophy in rats. Comparing muscle phenotypes, we found that long-term melatonin administration could influence muscle mass. Muscle atrophy-related genes, including muscle atrophy F-box (MAFbx) and muscle ring finger 1 (MuRF1) were significantly down-regulated in melatonin-administered rats in the gastrocnemius. However, only MAFbx at the mRNA level was attenuated in the soleus of melatonin-administered rats. Insulin-like growth factor-1 receptor (IGF-1R) was significantly over-expressed in melatonin-administered rats in both the gastrocnemius and soleus muscles. Comparing myosin heavy chain (MHC) components, in the gastrocnemius, expression of both slow- and fast-type isoforms were significantly enhanced in melatonin-administered rats. These results suggest that long-term exogenous melatonin-administration may have a prophylactic effect on muscle atrophy through the MuRF1/MAFbx signaling pathway, as well as a potential therapeutic effect on muscle atrophy through the IGF-1-mediated hypertrophic signaling pathway in a stroke animal model.

Keywords: Melatonin; focal cerebral ischemia; muscle atrophy.

Figure 1

Changes in muscle mass following melatonin administration for 8 weeks after MCAo. (A) Gastrocnemius, (B) Soleus. Right means to sound side hindlimb. Left means to affected side hindlimb. Rt: right hindlimb; Lt: left hindlimb; Con: control; Veh: MCAo+vehicle; MT7: MCAo+melatonin injection at 7:00; MT19: MCAo+melatonin injection at 19:00; MT7,19: MCAo+melatonin injection at 7:00 and 19:00. ^**P<0.01 vs. Con.

Figure 2

Morphology of hindlimb muscles following melatonin administration for 8 weeks after MCAo. Veh: MCAo+vehicle; MT7: MCAo+melatonin injection at 7:00; MT19: MCAo+ melatonin injection at 19:00; MT7,19: MCAo+melatonin injection at 7:00 and 19:00. Scale bar=100 µm.

Figure 3

Changes of muscle atrophy- and hypertrophy-related gene expression on stroke-induced muscle atrophy in the gastrocnemius (A) and soleus (B). MT7,19 rats showed inhibition of both MAFbx and MuRF1 mRNA expression and an increase in hypertrophic upstream molecules, such as IGF-1R expression. Con: control; Veh: MCAo+vehicle; MT7: MCAo+ melatonin injection at 7:00; MT19: MCAo+melatonin injection at 19:00; MT7,19: MCAo+melatonin injection at 7:00 and 19:00. (A) ^**P<0.01 vs. Con; ^##P<0.01 vs. Veh. (B) ^*P<0.05, ^**P<0.01 vs. Con; ^#P<0.05, ^##P<0.01 vs. Veh.

Figure 4

Changes of MHC components on stroke-induced muscle atrophy in the gastrocnemius (A) and soleus (B). MT7 and MT7,19 rats showed increases in both slow- and fast-type MHC isoforms. Con: control; Veh: MCAo+vehicle; MT7: MCAo+melatonin injection at 7:00; MT19: MCAo+melatonin injection at 19:00; MT7,19: MCAo+melatonin injection at 7:00 and 19:00. (A) ^*P<0.05, ^**P<0.01 vs. Con; ^#P<0.05, ^##P<0.01 vs. Veh. (B) ^*P<0.05, ^**P<0.01 vs. Con; ^#P<0.05, ^##P<0.01 vs. Veh.