Sarcopenia is the accelerated loss of muscle mass, strength, and function. It is associated with an increased risk of faster cardiovascular disease progression, death, falls, and decreased quality of life, especially in older adults13. As an emerging geriatric giant, sarcopenia poses a serious burden on global health14. There is an urgent need to further understand the pathogenesis, molecular markers, and treatment options for sarcopenia15. However, little is known about the phosphorylation network and kinase activity profiles of older adults with sarcopenia16. In our study, we performed global phosphoproteomics analysis of lumbar tissues from sarcopenia patients and healthy individuals, and established a global map of differentially regulated protein phosphorylation in sarcopenia patients. The aim was to elucidate the differential protein phosphorylation networks and identify signaling pathways involved in abnormal muscle metabolism, thereby finding potential targets for the treatment of sarcopenia.
In our study, we observed several phosphorylated proteins that may play important roles in muscle degeneration and could be potential therapeutic targets for sarcopenia patients. The TTN protein is in a very critical position in our protein network. Studies have shown that TTN gene mutations are associated with multiple skeletal myopathies and cardiomyopathies, the most prominent of which is dilated cardiomyopathy17. TTN protein can be modified in a variety of ways to perform different functions. Although phosphorylation is the most studied modification, a series of protein kinases can phosphorylate 377 multiple sites in TTN18, making the research very complex. TTN protein is the third most abundant myosin in the sarcomere19, providing passive stiffness to striated muscle sarcomeres and regulating active contractile force20. It is essential for normal sarcomere formation and plays a key role in maintaining the structural stability of muscle cells and active and passive sarcomere function21. However, the molecular mechanism has not been elucidated22, and further research is needed to confirm the role of TTN in muscle atrophy.
MYH7 is a slow ATPase myosin located in type I skeletal muscle fibers23. Mutations in MYH7 can lead to a variety of cardiomyopathies and myopathies, and can also affect tumorigenesis24. The pathological mechanisms of MYH7 have been gradually revealed, but are not yet fully understood25. MYH7 mutations can affect Ca2+ spatiotemporal regulation, leading to unstable sarcomere assembly or structural changes, disrupting the normal structure and stability of myosin, and eventually leading to the occurrence of various muscle diseases26.
We also predicted the upstream kinases VRK1, VRK2, UHMK1, and SGK3. These kinases have been shown to affect the development of various cancers. VRK1 is a serine/threonine kinase that phosphorylates a variety of transcription factors, including p53, histones, and proteins involved in the DNA damage response pathway. It is overexpressed in many types of tumors and is associated with poor prognosis [27]. UHMK1 is an oncogene in lung adenocarcinoma that exhibits strong oncogenic potential and exerts its biological effects through the phosphatidylinositol 3-kinase (PI3K)/protein kinase B(AKT)/mammalian target of rapamycin(mTOR) signaling pathway mechanism [28]. The specific molecular mechanisms by which these kinases affect muscle cells remain to be further studied.
Although we focused on lumbar cells from elderly individuals, our results suggest that some of the differentially phosphorylated proteins are also involved in signaling pathways of other heart diseases or aging-related diseases. This study has certain reference value for phosphoproteomics research of other aging-related diseases.