Identification Of A Long Non-coding RNA That Regulates Type I/β Myosin In Both Skeletal And Cardiac Muscle

Disuse of skeletal muscle results in a loss of slow type I myosin heavy chain (I-MHC) that is mediated by the transcriptional repression of the MYH7 gene. Conversely, compensatory hypertrophy in the heart causes transcriptional activation of MYH7. We discovered several long non-coding (lnc) RNAs by RACE PCR and sequencing that are transcribed from the antisense (AS) strand of the MYH7 gene, thus named MYH7-AS. Variants of MYH7-AS contain an exon that partially overlaps and is complementary to the microRNA (miR) 208b, which is encoded in a MYH7 intron. PURPOSE: to characterize the regulation of MYH7-AS and MYH7 in skeletal muscle in response to disuse and in cardiac muscle in response to compensatory hypertrophy. METHODS: We induced soleus muscle disuse atrophy in rats with 7 days of hindlimb unloading suspension (N = 6). Cardiac hypertrophy was induced by pressure overload in rats by ascending aortic banding (AB) for 16 days (N = 6). RNA expression was examined by real-time PCR. RESULTS: Muscle mass and MYH7 mRNA were significantly decreased (p < 0.05) in soleus after muscle unloading as compared to ambulatory control rat soleus, and there was a corresponding 6.5-fold increase in MYH7-AS. Cardiac mass (HW/BW ratio) was increased by 29% in response to AB. M-mode echocardiographic parameters of cardiac left ventricle (LV) at the time of sacrifice such as interventricular septal thickness (+24%) and LV free wall thickness (+32%) were similarly increased. MYH7 mRNA was significantly increased in LV after AB as compared to sham (2.1-fold), and there was a corresponding 4.2-fold less expression of MYH7-AS with AB. CONCLUSIONS: MYH7 and MYH7-AS expression was shown to be reciprocally altered by divergent stimuli in skeletal and cardiac muscle. A regulatory framework for Myh7-AS to inhibit Myh7 is supported in cardiac muscle and during skeletal muscle atrophy. Future research will determine if MYH7-AS could be utilized for exogenous delivery as a therapeutic approach to inhibit β-MHC upregulation in the hypertrophic heart and thereby preserve cardiac function and protect the heart from failure. Conversely, a strategy to preserve I-MHC in atrophied skeletal muscle could entail selective degradation of MYH7-AS, thereby rescuing or maintaining fatigue resistance in muscle afflicted by disuse, injury, or associated disease states. Research Eureka Accelerator Program provided by VCOM