The present study found that the cytokine levels might affect the number of sarcopenia components and sarcopenia severity. Accordingly, our results showed that, among elderly participants, more sarcopenia components were associated with decreased IL-12 and increased TGF-β levels. We speculate that these cytokines might have been partly released during macrophage polarization into M1 and M2 subtypes, which are involved in pro-inflammatory and anti‐inflammatory activities, respectively. To the best of our knowledge, the present study was the first to explore the relationships between cytokines and sarcopenia in a Taiwanese elderly population.
TGF-β has been proposed to induce skeletal muscle atrophy and fibrosis by regulating the activity of skeletal muscle satellite cell. Moreover, TGF-β has been suggested to lower muscle regeneration by inhibiting muscle cell differentiation and proliferation via the Smad-3 signaling system, which has been shown to prevent positive regulators of muscle cell differentiation, including MyoD and myogenin. Excessive TGF-β production has been considered the main cause of progressive tissue fibrosis and scar formation, leading to muscle loss and impaired muscle function. Moreover, studies have suggested that TGF-β plays a role in muscle impairment and fibrosis accompanying the aging process. Our findings are consistent with those presented in previous studies showing that sarcopenia is significantly associated with increased TGF-β levels.
IL-12 is a pro-inflammatory cytokine that promotes T cell proliferation and cytotoxic activity. Unfortunately, limited studies have been available regarding the role of IL-12 in myogenic differentiation. Romanazzo et al. demonstrated that IL-12 overexpression in C2C12 mouse skeletal muscle cells enhanced the myogenic differentiation process. IL-12 has been a well-known risk factor for Alzheimer's disease and cognitive aging[29, 30]. A population-based study of Taiwanese elderly participants, suggested that IL-12-associated genes caused the etiological changes observed during cognitive aging. Previous studies have also proposed a connection between IL-12 and physical activity. Accordingly, endurance exercise has been associated with the induction of Th2 cytokines, including IL-4 and IL-12, while Suzuki et al. demonstrated that IL-12 concentration significantly increased after maximal exercise. Moreover, a retrospective study of 16 men who participated in a running program showed that intense exercise enhances IL-12 levels in peripheral blood mononuclear cells. The present study found that lower IL-12 levels were associated with a higher occurrence of sarcopenia. Given the aforementioned findings, we speculate that patients with increased IL-12 levels may have better muscle strength and physical performance, as well as lower incidences of sarcopenia. Further experiments will be necessary to clarify the function of IL-12 in human skeletal muscle and the molecular mechanisms underlying its action.
Cui et al. had reported the role of macrophage polarization in skeletal muscle metabolism associated with aging, which is involved in the distinct macrophage function. Impaired macrophage activity during aging has been suggested to promote deterioration in satellite cell function and muscle regeneration. One study observed that the resting muscles of aged mice had increased M2 macrophages, accompanied by increased skeletal muscle fibrosis. Meanwhile, a human study showed that older patients had higher gene expression of M2 macrophages compared to the younger patients, suggesting an increase in the proinflammatory process with age. Moratal et al. demonstrated that M2 macrophages induced adipogenesis through fibro-adipogenic progenitors. By promoting fibrosis and fat infiltration, which are major features of skeletal muscle aging, macrophage polarization, especially M2 macrophages, may play an important role in the altered skeletal muscle function, and sarcopenia.
Some limitations in the present study are worth noting. First, the cross-sectional design of this study prevented the identification of causal relationships between cytokines and sarcopenia. Therefore, longitudinal studies are needed to explore whether cytokines can be utilized for the early diagnosis and evaluation of therapeutic interventions in sarcopenia. Second, flow cytometry, which measures specific protein expressions, has been the standard method for identifying macrophages. However, given that only a few macrophages were detected in the study samples, cytokines were obtained from participants’ blood samples to indicate macrophage activation. Next, considering that cytokines are potent mediators across various inflammatory states and age-related diseases, their measurements might have been affected by physiological and pathological changes. Therefore, macrophage polarization can only be an indirect predictor for evaluating muscle differentiation and sarcopenia. Finally, the sensitivity and specificity values are relatively low in the present study. The sensitivity and specificity of a quantitative test are dependent on the cutoff point above or below which the test is positive. If the cutoff point is raised, there are fewer false positives but more false negatives that the test is highly specific but not very sensitive.
The current study found that the number of sarcopenia components and sarcopenia severity were associated with plasma cytokines levels among older individuals. Furthermore, IL-12 had been found to be associated with the occurrence of sarcopenia, suggesting its potential as a muscle quality indicator for predicting outcomes of age-associated muscle loss. The combination of clinical practice and biomarker assessment in evaluating muscle quality may be essential for the early diagnosis of sarcopenia. Moreover, determining whether IL-12 can become a novel biological target for preventive and therapeutic interventions will be interesting. Nevertheless, the potential mechanisms through which macrophage function affects aging skeletal muscle remain unclear. Further studies are required to characterize the function of these cytokines and provide a basis for the better modulation of their signaling in therapeutic approaches.