Elevated IGFBP1 triggers musculoskeletal defects in mice

Here we showed that IGFBP1, a liver-derived hormone belonging to the insulin-like growth factor family of binding proteins (IGFBPs), plays a causative role in driving musculoskeletal complications. In our initial studies, IGFBP1 was found elevated in colorectal cancer (CRC) cachectic patients and in CRC hosts, along with muscle and bone loss. In vitro, IGFBP1 induced myotube atrophy and osteoclast differentiation. Therefore, the objective of this study was to define the mechanisms by which IGFBP1 contributes to muscle and bone depletion. Our central hypothesis is that elevated circulating (hepatic) IGFBP1 initiates events consistent with musculoskeletal wasting. We infected normal mice (without tumors) with adeno-associated viruses carrying the full-length IGFBP1 gene, injected via the tail vein. At time of sacrifice (after 54 days) the animals presented drastically elevated IGFBP1 circulating levels, along with severe loss of muscle and bone mass. In order to shed light on the IGFBP1-related effects in skeletal muscle only, we generated an RNAseq dataset in quadriceps muscles from animals infected with AAV-IGFBP1. Our study revealed modulation of several signaling pathways, in line with the cachectic phenotype. Therefore, our findings contribute to define the mechanistic effects of IGFBP1 in cachexia and identify IGFBP1 as a new therapeutic target for the treatment of the musculoskeletal complications of cancer.