ECTOPIC TWEAKR EXPRESSION IN TYPE I FIBER OF STROKE-PRONE SPONTANEOUSLY HYPERTENSIVE RATS IS RELATED TO SLOW MUSCLE-SPECIFIC HYPOTROPHY THROUGH MURF1 OVEREXPRESSION

Abstract

Objective: The maintenance of muscle strength and mass is important for body homeostasis. Stroke-prone spontaneously hypertensive rats (SHRSP) show significantly higher blood pressure and lower body weight than normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). In addition, blood pressure and body weight show an inverse correlation among the rats. We hypothesized that skeletal muscle hypotrophy in hypertensive rats is related to hypertension-related diseases and is useful as a therapeutic target for hypertension and hypertension-related diseases. We aimed to investigate the pathophysiological characteristics of muscle hypotrophy in SHRSP to determine the therapeutic target molecule(s). Design and method: First, the difference in skeletal muscles in the lower leg between WKY and SHRSP was evaluated mainly through weight/tibial length and histological analysis. Further experiments were carried out based on gene expression using microarray, protein expression, and immunohistochemistry analyses. Results: SHRSP had a significantly lower weight/tibial length in the soleus and gastrocnemius, but not in the plantaris and tibialis anterior. This suggests that muscles with a relatively high amount of slow muscle fiber (type I fiber) show hypotrophy. Histological analysis of the soleus, showing that type I fibers mainly decreased the fiber size, corresponded to the result of weight/tibial length. Microarray and protein expression analyses showed that the muscle-specific ubiquitin ligase, muscle RING finger 1 (MuRF1), but not atrogin-1, was highly expressed in the soleus, but not in the plantaris, in SHRSP. TNF-like weak inducer of apoptosis receptor (TWEAKR) was predicted as a MuRF1 up-regulator in the Ingenuity Pathway Analysis. There was no significant difference in TWEAKR expression level in the soleus between WKY and SHRSP. However, immunofluorescence revealed that WKY had only type II fiber staining, but SHRSP had both type I and II fiber staining. Conclusions: TWEAKR is a type II-specific receptor in the skeletal muscle. Ectopic TWEAKR expression in type I fibers of SHRSP is most likely involved in slow muscle-specific hypotrophy through MuRF1 overexpression. The TWEAKR-MuRF1 pathway may be a useful therapeutic target for slow muscle hypotrophy.