Growth hormone/IGF-I-dependent signaling restores decreased expression of the myokine SPARC in aged skeletal muscle

Abstract

Abstract Skeletal muscle exerts many beneficial effects on the human body including the contraction-dependent secretion of peptides termed myokines. We have recently connected the myokine secreted protein acidic and rich in cysteine (SPARC) to the formation of intramuscular adipose tissue (IMAT) in skeletal muscle from aged mice and humans. Here, we searched for inducers of SPARC in order to uncover novel treatment approaches for IMAT. Endurance exercise in mice as well as forskolin treatment in vitro only modestly activated SPARC levels. However, through pharmacological treatments in vitro, we identified IGF-I as a potent inducer of SPARC expression in muscle cells, likely through a direct activation of its promoter via phosphatidylinositol 4,5-bisphospate 3-kinase (PI3K)-dependent signaling. We employed two different mouse models of growth hormone (GH)/IGF-I deficiency to solidify our understanding of the relationship between IGF-I and SPARC in vivo. GH administration robustly increased intramuscular SPARC levels (3.5-fold) in GH releasing hormone receptor-deficient mice and restored low intramuscular SPARC expression in skeletal muscle from aged mice. Intramuscular glycerol injections induced higher levels of adipocyte markers (adiponectin, perilipin) in aged compared to young mice, which was not prevented by GH treatment. Our study provides a roadmap for the study of myokine regulation during aging and demonstrates that the GH/IGF-I axis is critical for SPARC expression in skeletal muscle. Although GH treatment did not prevent IMAT formation in the glycerol model, targeting SPARC by exercise or by activation of IGF-I signaling might offer a novel therapeutic strategy against IMAT formation during aging. Key messages IGF-I regulates the myokine SPARC in muscle cells directly at the promoter level. GH/IGF-I is able to restore the decreased SPARC levels in aged skeletal muscle. The glycerol model induces higher adipocyte markers in aged compared to young muscle. GH treatment does not prevent IMAT formation in the glycerol model.