IGF signaling has been shown to

IGF-1 signaling has been shown to induce nucleoside analog changes via interacting with MKK-p38 signaling (Serra et al., 2007) and by perturbing Foxo3a signaling (Stitt et al., 2004), among other mechanisms. The current study demonstrates that the acetyl group itself may be limiting, since IGF-1/ACL/acetyl-CoA signaling can regulate H3K9/14 and H3K27 acetylation. This may have further implications for other pathways where H3K9 and H3K27 acetylation plays a prominent role, including DNA damage; that will be the subject for future studies. The prior demonstration that ACL controls mitochondrial efficiency (Das et al., 2015) and now that it regulates both differentiation and the degree of regeneration clearly show that the IGF-1/Akt/ACL-signaling node is critical for muscle function and repair, and they suggest that activation of ACL in settings of muscle injury would be beneficial.
Experimental Procedures
Author Contributions S.D. and M.F. conceived and designed the experiments and analyzed the data. S.D. contributed to the execution of the in vitro experiments and sample analysis of animal experiments. F.M., G.T., and P.B. contributed to the design, execution, and analysis of animal experiments. G.C.M. contributed to the design, execution, and analysis of SC experiments, and H.R. contributed to the execution of SC experiments. G.M. and B.J. contributed to the execution of the in vitro experiments. P.K. analyzed gene expression in some of the in vitro experiments. M.F. supervised the project. D.J.G. contributed to the design of the experiments. S.D., M.F., and D.J.G. co-wrote the manuscript. S.D. and G.M. are the recipients of NIBR postdoctoral fellowships.
Acknowledgments We thank the Muscle Diseases group at the Novartis Institutes for Biomedical Research (NIBR, Basel, Switzerland) for its support.
Increasing evidence shows that, in addition to providing essential energy, metabolic flux actively participates in numerous processes, including development, stem cell homeostasis, and regeneration . Metabolic dysregulation is closely associated with disorders such as obesity and cancer . Acetyl-CoA, a metabolic intermediate used in mitochondria energy production, is required for the synthesis of cholesterol and fatty acid in the cytosol because it provides a carbon source. It is also used in histone and other protein acetylation by providing acetyl groups , . ACL is the enzyme that catalyzes the generation of acetyl-CoA and oxaloacetate from citrate in the presence of ATP and CoA. This reaction is responsible for the extramitochondrial acetyl-CoA production . By linking glucose metabolism to macromolecular biosynthesis and epigenetics, ACL has been described to be involved in embryonic growth, liver homeostasis, and cancer cell proliferation, as well as metabolic disorders, including hyperlipidemia . However, whether ACL functions in nonliver tissues, such as skeletal muscle, is still poorly understood. Skeletal muscle strengthening and contraction are energy-consuming processes, and skeletal muscle mass is directly linked with muscle metabolism. Exercise is often helpful for improving muscle function by increasing metabolic capacity, indicating that metabolic changes somehow regulate muscle function. Interestingly, ACL activation induced through the IGF1/PI3K/AKT pathway increases cardiolipin synthesis and mitochondrial supercomplex activity, which ultimately enhances mitochondrial function in skeletal muscle . However, whether muscle stem cells, also known as satellite cells (SCs), and muscle regeneration are affected by ACL remains to be determined. A recent paper by Das sheds light on ACL specific functions in skeletal muscle by revealing that ACL/acetyl-CoA modulates SC differentiation and muscle regeneration by affecting histone acetylation level at gene regulatory regions . In both mouse and human myoblasts, Das observed that reducing ACL selectively decreased fast myosin (fast MyHC, MYH1) expression and increased slow myosin (slow MyHC, MYH7) expression. In experiments, overexpression of ACL did not alter SC proliferation, but rather promoted their differentiation, resulting in increased fast myosin expression and myotube size. By contrast, ACL knockdown inhibited SC differentiation ().