Identification of a senescence-associated transcriptional program in skeletal muscle of cachectic pancreatic-tumor-bearing mice.

Abstract

Cancer cachexia is the involuntary loss of body and skeletal muscle mass, which negatively impacts physical function, quality of life, treatment tolerance, and survival. Skeletal muscles of cachectic people and mice with pancreatic tumors also exhibit skeletal muscle damage, nonresolute immune cell infiltration, and impaired regeneration. These phenotypes may be influenced by the accumulation of senescent cells, which secrete factors detrimental to skeletal muscle health. However, there is currently no comprehensive research on the senescent cell accumulation in the skeletal muscle of tumor-bearing hosts, with or without chemotherapy. To address this gap, we cross-referenced the SenMayo panel of 125 senescence-related genes with our RNA-seq dataset in mouse skeletal muscle during the initiation and progression of cancer cachexia, which revealed a differential expression of 39 genes at precachexia, 64 genes at cachexia onset, and 72 genes when cachexia is severe. Since p16 is a canonical marker of senescence, we subsequently orthotopically injected p16-tdTomato reporter mice with murine KPC pancreatic cancer cells and treated a subset of mice with chemotherapy. At experimental endpoint, when KPC treatment-naïve mice were cachectic, we observed an increased accumulation of p16+ cells, along with increased mRNA levels of hallmark senescence markers (Cdkn1a/p21, Cdkn2a/p16, Glb1/senescent-associated-β-galactosidase), which were exacerbated by chemotherapy. Finally, we demonstrate an increase in CDKN1A/p21 in the muscle of cachectic patients with pancreatic cancer, which associated with cachexia severity. These findings suggest that senescent cells accumulate in skeletal muscle of cachectic pancreatic tumor-bearing hosts and that chemotherapy can exacerbate this accumulation.NEW & NOTEWORTHY To the best of our knowledge, this study is the first to investigate senescent cell accumulation in skeletal muscle of tumor-bearing hosts and its exacerbation by chemotherapy. Our findings identify an accumulation of senescent cells and reveal a senescence-related transcriptional program in skeletal muscle during the initiation and progression of cancer cachexia that is exacerbated by chemotherapy treatment. This highlights a novel potential therapeutic mechanism that can be targeted for the prevention of cancer-induced muscle pathologies.