The long noncoding RNA lnc-H19 is important for endurance exercise by maintaining slow muscle fiber types

Abstract

Skeletal muscle consists of different muscle fiber types whose heterogeneity is characterized by different metabolic patterns and expression of MyHC isomers. The transformation of muscle fiber types is regulated by a complex molecular network in which long noncoding (lnc) RNAs play an important role. In this study, we found that lnc-H19 is more enriched in slow muscle fibers. In vitro, interference of lnc-H19 by siRNA significantly promoted the expression of fast muscle fiber gene MyHC IIB and inhibited the expression of the slow muscle fiber gene MyHC I, thereby leading to a fast muscle fiber phenotype. In addition, interference of lnc-H19 significantly inhibited mRNA expression of the mitochondrial genes, such as COX5A, COX-2, UQCRFSL, FABP3, and CD36. Overexpression of lnc-H19 resulted in an opposite result. In vivo, knockdown of lnc-H19 by AAV-shRNA-H19 suppressed the mRNA expression of the slow muscle fiber gene MyHC I and the protein expression of slow-MyHC. Simultaneously, mitochondria were reduced in number, swollen, and vacuolated. The activities of succinate dehydrogenase, lactic dehydrogenase, and superoxide dismutase were significantly inhibited, and malondialdehyde content was significantly increased, indicating that deficiency of lnc-H19 leads to decreased oxidative metabolism and antioxidant capacity in muscle. Furthermore, inhibition of lnc-H19 decreased the weight-bearing swimming time and limb suspension time of mice. In conclusion, our results revealed the role of lnc-H19 in maintaining slow muscle fiber types and maintaining exercise endurance, which may help to further improve the regulatory network of lnc-H19 in muscle function.