In Aging Cell, researchers have discovered a potential way to use a microRNA to diagnose sarcopenia, the age-related loss of muscle.
Primary and secondary sarcopenia
Previous research has been able to distinguish sarcopenia by its sources. Primary sarcopenia directly comes from the processes of aging, while secondary sarcopenia is a side effect of such things as poor nutrition, atrophy from disuse, and both acute and chronic diseases [1]. The researchers of this study note that the difference is difficult to distinguish in the clinic, where these two categories heavily overlap.
Heart failure, which is defined here as a progressive clinical syndrome [2] rather than an effect of acute causes such as heart attack, is heavily associated with sarcopenia [3]. A substantial amount of other work has shone some light on this relationship, and these problems share many of the same causes [4].
Looking for a way to diagnose the true causes of sarcopenia in the context of heart failure, these researchers have turned to microRNAs, non-coding RNA molecules that affect gene transcription and have been used to investigate the sources of diseases, including sarcopenia in the context of obesity [5]. One of these microRNAs is microRNA-22-3p (miR-22), which is found in many species and is expressed predominantly in muscle tissue and nerves [6]. This suggests a possible use in diagnostics and therapies, and work has been done in using it as a treatment for heart attack [7].
The biological effects of miR-22 vary by tissue. Some work has found that it blocks calcium uptake in a way that leads to diminished heart contraction ability [8]. Other work has found that it suppresses proliferation while encouraging differentiation in skeletal muscle cells, and inhibiting it does the opposite [9]. Work in mice has revealed that miR-22 in exosomes, which cells use to send signals to one another, leads to insulin resistance [10]. These researchers also performed their own in silico pathway analysis, which confirmed that it impacts an enormous network of metabolic and age-related pathways, many of which are related to aging.
Two studies create a combined picture
These researchers evaluated data from the SPRINTT study, which recruited 61 people aged 70 or older. Half of the participants showed signs of sarcopenia, which SPRINTT defined as a pre-disability state defined by gradual muscle failure and measured using a significant absence of lean mass. People with advanced heart conditions and other serious age-related disorders, such as cancer and dementia, were excluded. While that study focused on technological and nutritional interventions rather than microRNAs, it still took biomarker data from its participants. SPRINTT was intended to evaluate people with primary sarcopenia.
Other data came from SICA-HF, which recruited 176 people with heart failure of all ages. Like SPRINTT, its basis for a sarcopenia diagnosis was the absence of sufficient muscle mass. The reearchers used SICA-HF as their basis for secondary sarcopenia.
Using data from the SPRINTT study, the researchers found that people with primary sarcopenia have significantly more miR-22 than people without it. This difference was not found in other microRNAs that the researchers analyzed. Using this data, they determined that it was possible to develop a miR-22-based test that could be used to screen for sarcopenia, although such a test would not be completely perfect.
Interestingly, however, the opposite was true for secondary sarcopenia, with people with sarcopenia in the SICA-HF study being more likely to have less miR-22. While this data was somewhat weaker than the results derived from SPRINTT, it still reached the level of statistical significance.
The combination of these results leads these researchers to believe that miR-22 is a potentially useful diagnostic tool for the evaluation of primary versus secondary sarcopenia. They offer a few plausible reasons why this may be the case, suggesting that the source of the circulating miR-22 (cardiac or skeletal muscle) may be the primary difference [11] and that miR-22 may play different roles in these muscle types. The researchers also suggest that the effects of miR-22 on differentiation and proliferation, leading to changes in its regulation, may be involved. Furthermore, the correlation between miR-22 and sarcopenia in the cardiac patients may be due to an upstream cause rather than a direct relationship.
These researchers further acknowledge that there are limitations in using two separate studies to create a conclusion based on both of them. Those studies did not define sarcopenia in exactly the same way, and there is still the issue of overlapping causes. Therefore, substantial further work must be done in order to determine how microRNAs relate to this muscle-wasting condition.
Literature
[1] Cruz-Jentoft, A. J., Bahat, G., Bauer, J., Boirie, Y., Bruyère, O., Cederholm, T., … & Zamboni, M. (2019). Sarcopenia: revised European consensus on definition and diagnosis. Age and ageing, 48(1), 16-31.
[2] Tomasoni, D., Adamo, M., Lombardi, C. M., & Metra, M. (2019). Highlights in heart failure. ESC heart failure, 6(6), 1105-1127.
[3] Fülster, S., Tacke, M., Sandek, A., Ebner, N., Tschöpe, C., Doehner, W., … & von Haehling, S. (2013). Muscle wasting in patients with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure (SICA-HF). European heart journal, 34(7), 512-519.
[4] Sato, R., Vatic, M., Peixoto da Fonseca, G. W., Anker, S. D., & von Haehling, S. (2024). Biological basis and treatment of frailty and sarcopenia. Cardiovascular research, 120(9), 982-998.
[5] Dowling, L., Duseja, A., Vilaca, T., Walsh, J. S., & Goljanek‐Whysall, K. (2022). MicroRNAs in obesity, sarcopenia, and commonalities for sarcopenic obesity: a systematic review. Journal of Cachexia, Sarcopenia and Muscle, 13(1), 68-85.
[6] Huang, Z. P., & Wang, D. Z. (2018). miR-22 in smooth muscle cells: a potential therapy for cardiovascular disease. Circulation, 137(17), 1842-1845.
[7] Gupta, S. K., Foinquinos, A., Thum, S., Remke, J., Zimmer, K., Bauters, C., … & Thum, T. (2016). Preclinical development of a microRNA-based therapy for elderly patients with myocardial infarction. Journal of the American College of Cardiology, 68(14), 1557-1571.
[8] Gurha, P., Wang, T., Larimore, A. H., Sassi, Y., Abreu-Goodger, C., Ramirez, M. O., … & Rodriguez, A. (2013). microRNA-22 promotes heart failure through coordinate suppression of PPAR/ERR-nuclear hormone receptor transcription. PLoS One, 8(9), e75882.
[9] Wang, S., Cao, X., Ge, L., Gu, Y., Lv, X., Getachew, T., … & Sun, W. (2022). MiR-22-3p inhibits proliferation and promotes differentiation of skeletal muscle cells by targeting IGFBP3 in Hu sheep. Animals, 12(1), 114.
[10] Zhang, H., Zhang, X., Wang, S., Zheng, L., Guo, H., Ren, Y., … & Yan, Y. (2023). Adipocyte-derived exosomal miR-22-3p modulated by circadian rhythm disruption regulates insulin sensitivity in skeletal muscle cells. Journal of Biological Chemistry, 299(12).
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