9215 Role Of Insulin/IGF1 Signaling And FoxO Transcription Factors In Satellite Cell And Skeletal Muscle Development And Senescence

Abstract

Abstract Disclosure: Y. Yu: None. G. Wang: None. B.T. O'Neill: None. C.R. Kahn: None. Aging is associated with loss of skeletal muscle mass, deficiency of satellite cell (SC) function, and increase in intramuscular adipose tissue (IMAT) and insulin resistance posing threats to health and quality of elder life. Insulin / IGF1 signaling and their downstream signaling pathways play crucial roles in muscle function, as well as longevity a broad range of species. To identify the role of Insulin / IGF1 signaling in skeletal muscle homeostasis and aging/senescence, we took advantage of Cre-loxp mouse model using Pax7-Cre or HAS-Cre mice cross with insulin receptor (IR) and IGF1 receptor (IGF1R) double flox mice to create IR/IGF1R double knockout mice in both muscle progenitors (satellite cells) and mature skeletal muscle cells. We refer to the PaxCreIRIGF1RKO as the P7DKO and HSACreIRIGF1RKO as simply the DKO. Both P7DKO and DKO mice show severe loss of skeletal muscle with increased markers of cellular senescence and increased IMAT infiltration. This was indicated by a 60% loss of muscle mass, morphological evidence of skeletal muscle with atrophy and increased adipocyte infiltration, with a >6-fold increase of adipocyte marker Perlipin1. The muscle also exhibited 2- to 10-fold increases of cellular senescence and senescence-associated secretory markers, including Cdkn1a, Cdkn2a, Trp53, CD68, Cxcl14, and Ccr2. Both the whole skeletal muscle and primary satellite cells isolated from P7DKO mouse muscle show a higher level of senescence-associated beta-galactosidase, as compared to the cells from littermate controls. This was accompanied by a deficiency of proliferation and differentiation of the satellite cells. Interestingly, simultaneous knockout of Foxo1/3/4 in the DKO mouse muscle rescued the muscle atrophy, reduced IMAT infiltration and reduced skeletal muscle cell senescence. Thus, insulin/IGF1 signaling in satellite cells and mature muscle cells plays not only an important role in skeletal muscle development, but also skeletal muscle cell senescence, and this is mediated, in large part, through FOXO transcription factors. This pathway and these proteins provide both new insights and potential targets for improving skeletal muscle homeostasis and function in the elderly. Presentation: 6/2/2024