Serological muscle loss biomarkers: an overview of current concepts and future possibilities

Abstract

Background: The skeletal muscle mass is the largest organ in the healthy body, comprising 30-40 % of the body weight of an adult man. It confers protection from trauma, locomotion, ventilation, and it represents a "sink" in glucose metabolism and a reservoir of amino acids to other tissues such as the brain and blood cells. Naturally, loss of muscle has dire consequences for health as well as functionality. Muscle loss is a natural consequence of especially aging, inactivity, and their associated metabolic dysfunction, but it is strongly accelerated in critical illness such as organ failure, sepsis, or cancer. Whether this muscle loss is considered a primary or secondary condition, it is known that muscle loss is a symptom that predicts morbidity and mortality and one that is known to impact quality of life and independence. Therefore, monitoring of muscle mass is relevant in a number of pathologies as well as in clinical trials as measures of efficacy as well as safety.

Methods and results: Existing biomarkers of muscle mass or muscle loss have shown to be either too unreliable or too impractical in relation to the perceived clinical benefit to reach regular clinical research or use. We suggest serological neoepitope biomarkers as a possible technology to address some of these problems. Blood biomarkers of this kind have previously been shown to respond with high sensitivity and shorter time to minimum significant change than available biomarkers of muscle mass. We provide brief reviews of existing muscle mass or function biomarker technologies, muscle protein biology, and existing neoepitope biomarkers and proceed to present tentative recommendations on how to select and detect neoepitope biomarkers.

Conclusion: We suggest that serological peptide biomarkers whose tissue and pathology specificity are derived from post-translational modification of proteins in tissues of interest, presenting so-called neoepitopes, represents an exciting candidate technology to fill out an empty niche in biomarker technology.

Fig. 1

Overview of net and gross protein synthesis and degradation rates in muscle during various conditions or states. The figure clearly shows that in all but the most critically ill, net protein metabolism (whether it is net synthesis or net degradation) is vastly smaller than gross degradation or synthesis. Hence, a good biomarker or panel of biomarkers should reflect net degradation or synthesis

Fig. 2

The dynamics of responses of biomarkers with different sensitivities to change. Muscle mass or function in itself changes slowly and thus biomarkers of muscle mass or function (blue line) will take a long time to detect minimal significant change. A biomarker responsive to the process of muscle loss (red line), rather than muscle mass or function in itself will, if reliable enough, require a much shorter time to MSC

Fig. 3

Pictogram showing how tissue and pathology specificity of parent proteins and PTMs combine to form neoepitope biomarkers that are indicative of ongoing processes rather than conditions or states

Fig. 4

Figure showing how modifications to protein introduces another constraint to abundance, and produces new “tags” which eases detection by antibody or MS-based methods

Fig. 5

Overview of the sarcomere structure and some of the most abundant structural proteins therein. The myosin thick filaments are seen protruding from the M-disk, whereas the actin filaments are seen protruding from the Z-disks. The sarcomere structure is shared between skeletal and cardiac muscle, but some of the genes present are different isoforms. Reprinted from [81]. PubMed Central was the original publisher and the reprint is used in accordance with PubMed Central’s open access charter

Fig. 6

This figure shows the structure of the costamere and known molecular interactions. Below the membrane bilayer shown is the intracellular space and above it is the extracellular space. In the intracellular space, the costamere is attached to the contractile proteins through dystrophins (for the dystrophin glycoprotein complex, DGC), vinculin, talin, and paxilin (for the integrin complexes; not shown). In the extracellular space, both DGCs and integrin complexes bind to components of the basal lamina that is attached to the rest of the extracellular matrix that consists mostly of fibrillar collagens. Reprinted from [82] with permission from Elsevier