**13. Conclusions**

We review the role of IGF-1 and its downstream signaling in skeletal muscle atrophy associated with various chronic diseases and aging. IGF-1 regulates skeletal muscle protein synthesis and protein degradation via the UPS and autophagy, and multiple pathways and mechanisms have been identified (Figure 1). IGF-1 has also been shown to activate satellite cell proliferation, although the involvement of these cells in atrophy development in in vivo animal models and human patients remains to be elucidated. One of the di fficulties in IGF-1 research in skeletal muscle is that IGF-1 regulates numerous biological pathways, and these pathways likely interact with each other. For instance, growing evidence suggests the involvement of di fferent miRNAs in IGF-1 signaling, and, considering that each miRNA can target multiple mRNAs, careful examination of changes and biological functions of these miRNAs will be required. Furthermore, it is possible that delivering a specific isoform of IGF-1 may be required to have e ffective activation of downstream signaling. The role and relative importance

of IGF-1 signaling likely differs between muscle atrophy models, and further studies are required to develop effective strategies to apply IGF-1 to treat muscle atrophy in human patients.

**Funding:** This study was funded by NIH/NHLBI (R01HL080682 and R01HL070241), NIH/NIGMS (P30GM103337, U54GM104940 and 20GM103629), and American Heart Association (15SDG25240022 and 19TPA34850165).

**Conflicts of Interest:** The authors declare no conflict of interest.
