Knowing Both a Great Deal and Too Little About the Mechanisms of Sarcopenia

Today's open access paper is a tour of the better known mechanisms of post-translational modification of proteins, and their relevance to the universal age-related loss of muscle mass and strength, the onset of sarcopenia. It is a good example of the state of knowledge in much of the life sciences, where it is possible to know both a great deal and very little about an important topic such as maintenance of muscle tissue.

Thus one can find any number of papers in which specific mechanisms of post-translational modification when applied to specific proteins are investigated in connection to the regulation of muscle growth or maintenance of structures important to muscle strength, such as neuromuscular junctions. But at the end of the day, the forest obscures the trees: there is no unified, detailed understanding as to how it all comes together. Researchers cannot in fine detail describe the progression of muscle aging at the level of cellular biochemistry and show all of the relevant post-translational modifications fit into that picture.

Every paper describes a tiny part of the whole. The synthesis of present day knowledge will be a project of the century ahead. We can only point to the known causes of aging, find ways to intervene, and then reinforce those lines of development that prove to be more successful. In the case of sarcopenia, we know that stem cell function is important, and that is is impacted by causes of aging such as mitochondrial dysfunction and cellular senescence. That is perhaps a place to start, bypassing the very incomplete picture of regulation of muscle growth and maintenance in favor of simpler approaches that may credibly restore stem cell activity in aged muscle tissue.

Post-translational regulation of muscle growth, muscle aging and sarcopenia

Post-translational modifications (PTMs) such as phosphorylation, acetylation, and ubiquitination play critical roles in regulating signalling pathways that control muscle protein synthesis and degradation during muscle growth. However, during muscle aging, PTMs such as oxidation and glycation can lead to the accumulation of damaged proteins and impair muscle function. Specifically, oxidative stress can increase protein carbonylation and reduce the activity of key muscle proteins. The role of PTMs in sarcopenia is complex. Phosphorylation, acetylation and methylation can impact the activity of crucial proteins involved in muscle protein synthesis and degradation, whereas glycation and advanced glycation endproduct (AGE) formation can contribute to the accumulation of damaged proteins and affect muscle function.

Although this review provides an overview of the role of several PTMs in muscle homeostasis, it is important to note that there may be other types of modifications that also play a significant role in regulating muscle function, such as cysteine oxidation, ADP-ribosylation, and neddylation. High-throughput profiling of protein modifications associated with muscle mass, strength and functions helps us to understand the pathogenesis of sarcopenia and explore new diagnostic and therapeutic strategies, for example, the use of serological peptide biomarkers derived from PTM of proteins in tissues of interest for diagnosing skeletal muscle injury.

In addition, crosstalk between PTMs in physio-pathological processes of muscle, such as muscle aging and sarcopenia, remains to be investigated. The order and timing of protein modifications may be important for specific cellular processes, such as signal transduction. In these cases, sequential modifications may create a molecular 'switch' that controls the downstream signalling pathway or signal output. For instance, ubiquitination followed by phosphorylation can target a protein for degradation, whereas phosphorylation followed by acetylation can alter protein-protein interactions.Therefore, elucidating PTM crosstalk based on large-scale clinical samples is important for precision medicine in muscle diseases.