Transcriptomic characterization of the aberrant alternative splicing in skeletal muscles of sarcopenia patients.

Abstract

Sarcopenia represents a substantial health risk for the expanding elderly population globally, characterized by a progressive decline in skeletal muscle mass and strength as people age. To investigate the potential role of the alternative splicing change in sarcopenia pathogenesis, we conducted a re-analysis of previously published RNA-seq data from muscle biopsies of sarcopenia patients, age-matched healthy controls, and individuals exhibiting partial symptoms (either low muscle mass or reduced muscle function). Our results revealed 2260 differential alternative splicing events (DASEs) in 1686 genes (DASGs, differentially alternatively spliced genes) in sarcopenia samples, which included CD38, PARP, sirtuins involved in NAD biosynthesis and metabolism. These DASGs were significantly enriched in functional pathways critical for skeletal muscle development and sarcopenia pathogenesis, such as FoxO, neurotrophin and AMPK signaling. Notably, approximately half of these DASGs were also present in individuals with partial symptoms. Furthermore, we developed a sarcopenia mouse model by administering dexamethasone to C57BL/6 mice. RNA-seq and RT-qPCR analysis of differential alternative splicing in the transcriptomes of this mouse model revealed that some sarcopenia-related DASEs, including those in AKT2, MNL2, TCF7L2, and USP40, were conserved between humans and mice. Additionally, nearly 20% of the DASGs identified in sarcopenia mice overlapped with those from sarcopenia patients. Our integrated analyses reveal a core set of conserved alternative splicing abnormalities in sarcopenia that are shared between humans and mice, highlighting their potential as cross-species therapeutic targets.