Reduced nuclear translocation of serum response factor is associated with skeletal muscle atrophy in a cigarette smoke-induced mouse model of COPD

Ran Ma, Xuefang Gong, Hua Jiang, Chunyi Lin, Yuqin Chen, Xiaoming Xu, Chenting Zhang, Jian Wang, Wenju Lu, Nanshan ZhongGuangzhou Institute of Respiratory Disease, State Key Laboratory of Respiratory Diseases, The 1st Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong, People’s Republic of ChinaAbstract: Skeletal muscle atrophy and dysfunction are common complications in the chronic obstructive pulmonary disease (COPD). However, the underlying molecular mechanism remains elusive. Serum response factor (SRF) is a transcription factor which is critical in myocyte differentiation and growth. In this study, we established a mouse COPD model induced by cigarette smoking (CS) exposure for 24 weeks, with apparent pathophysiological changes, including increased airway resistance, enlarged alveoli, and skeletal muscle atrophy. Levels of upstream regulators of SRF, striated muscle activator of Rho signaling (STARS), and ras homolog gene family, member A (RhoA) were decreased in quadriceps muscle of COPD mice. Meanwhile, the nucleic location of SRF was diminished along with its cytoplasmic accumulation. There was a downregulation of the target muscle-specific gene, Igf1. These results suggest that the CS is one of the major cause for COPD pathogenesis, which induces the COPD-associated skeletal muscle atrophy which is closely related to decreasing SRF nucleic translocation, consequently downregulating the SRF target genes involved in muscle growth and nutrition. The STARS/RhoA signaling pathway might contribute to this course by impacting SRF subcellular distribution. Keywords: SRF, chronic obstructive pulmonary disease, skeletal muscle atrophy, cigarette smokin