Our investigations revealed that morbid soreness symptoms were prevalent in FM. As compared with exercise-related soreness, several characteristics of the non-exertional soreness in FM were identified in terms of clinical manifestations, distribution, and metabolomic features[5, 23] (Table 1). Additionally, phenotypes, therapeutic responses and metabotypes distinctly differed between FM patients with different severity of soreness symptoms (Table 2). Of note, the morbid soreness phenotypes in FM did not involve lactate accumulation but might be associated with excessive oxidative stress.
Muscle soreness results in intolerance to daily activity and thus prevents individuals from participating in daily activities or rehabilitation. In research of soreness, post-exercise soreness is mostly investigated, including acute post-exercise soreness and DOMS. The morbid soreness in FM shows several similarities as post-exercise conditions. First, both conditions show significant correlations of soreness and pain intensity[1, 24]. Moreover, post-exercise soreness limits range of motion and results in stiffness[25–27]. Similarly, soreness intensity and stiffness severity were positively correlated in FM. Additionally, limb stretch and massage help relieve symptoms in both conditions[1, 5, 27, 28]. However, several divergences exist too. Unlike in DOMS, the symptoms of FM do not involve tissue inflammation or mechanical insults[1, 7, 29]. Also, post-exercise soreness is a transient physiological response to exercise, whereas FM is a chronic pain condition resulting from aberrant central sensitization[1, 4, 7]. Additionally, we found no spatial correlation of pain and soreness symptoms in the affection regions of FM (Fig. 1C), which is quite different from the concordant manifestations of pain and soreness in the post-exercise conditions[5, 29]. In this sense, the investigations of non-exertional soreness in FM may provide a unique approach to probe the soreness nosography that previous DOMS research did not provide[1, 3, 29, 30]. A comparison of non-exertional and exertional soreness is summarized in Table 2.
Lactate accumulation in muscles is commonly thought to be associated with acute soreness after exercise[29, 31]. However, our investigation did not suggest upregulated lactate expression in FM individuals as compared with HCs. On the contrary, lactate expression was even lower in FM individuals with prominent soreness symptoms (FM-PS). Thus, the morbid soreness in FM may not involve lactate production, and the soreness mechanisms might differ from those in exercise conditions. Of note, oxidative status was significantly increased in FM-PS patients (Fig. 3B). In this context, the soreness symptoms in FM may not result from lactate accumulation but might involve other factors related to oxidative stress, such as oxidized products of lipids (e.g., lysophosphatidylcholine) or proteins (e.g., protein carbonyls)[32, 33]. Notably, for exertional soreness, antioxidants have been proposed to treat post-exercise soreness by reducing free radical generation during exercise[23, 34]. However, a recent systematic review did not strongly support the therapeutic efficacy on exertional soreness. Because of the excessive oxidative stress in FM and its correlation with soreness, antioxidants might be of potential therapeutic use to relieve the non-exertional soreness of FM, especially considering that current treatment cannot ameliorate soreness symptoms effectively in FM.
Patients with higher soreness intensity had more difficulty sitting still for 45 min (Tables S3 and S8). The restless conditions are reminiscent of the core feature of restless leg syndrome (RLS), another common comorbidity of FM[36, 37]. Up to one-third of patients with FM reported comorbid RLS symptoms. Coincidentally, soreness sensation is also a prevalent descriptor of RLS discomforts (40.4%). Like RLS, limb stretching also helps to alleviate the discomforts of FM, especially in FM-PS[39, 40]. So far, the clinical or pathophysiological associations among non-exertional soreness, RLS and FM remains undetermined. Future study is warranted to investigate the prevalence and clinicoetiologic correlates of these two disorders with focus on soreness manifestations.
FM features various symptomatic discrepancies of pain and soreness. For example, soreness diffuseness was fairly correlated with its intensity, but this correlation was not observed in pain conditions. Also, conventional therapies could effectively reduce WPI but not WSI (Table S4). Furthermore, soreness and pain had different clinical impacts on FM symptoms and disease severity. For example, pain symptoms were significantly associated with skin allodynia, sleep disturbance and fatigue, which suggests that coexisting pain symptoms might worse these comorbidities (Table S3). By comparison, soreness symptoms involved stiffness rather than the above conditions. These differences between soreness and pain may result from the potential differences in their somatosensory mechanisms[2, 7, 29].
FM is considered a heterogenous condition. We found distinct phenotypic differences between FM-P and FM-PS in terms of clinical presentation, therapeutic responses, metabolomic expression and oxidative stress status (Table 2). We found significant positive correlations between pain and soreness symptoms in FM-PS, with no similar findings for FM-P (Fig. S3A and 3B). Also, the impact of pain symptoms on the FM comorbidities was evident in FM-P but not FM-PS (Table S9). Moreover, we found remarkable differences in therapeutic responses in pain and soreness symptoms between the two groups (Fig. 1I and 1J). Notably, in FM-PS, conventional treatment successfully alleviated pain intensity but did not improve symptom severity or FIQR scores as compared with FM-P (Table S10). Such a discrepancy of therapeutic responses might result from the ineffective relief of soreness symptoms in FM-PS under current treatment. Accordingly, tailored therapeutic trials focusing on non-exertional soreness (e.g., antioxidants or non-steroidal anti-inflammatory drugs) are indicated, especially for patients with prominent soreness complaints.
We identified metabolomic differences between FM-P and FM-PS. The fold change analyses (Fig. 1A-B), sPLS-DA (Fig. S5B) and metabolomic heatmap (Fig. 2C-D) findings all suggest a more distinct metabolomic expression in FM-PS than FM-P versus HCs. Along with the findings of clinical manifestations, the evaluation of soreness in FM provides an easy approach to identify FM phenotypes, thereby benefiting patient classification and better therapeutic strategies.
Besides lactate, several metabolites are dysregulated in FM. Among the five metabolites identified by the pathway analysis, hypoxanthine, L-arginine and 2-oxoglutarate participate in oxidative stress generation and were downregulated concordantly. All three substances can function as source materials to produce endogenous oxidative and nitrosative stress. Hypoxanthine is the breakdown product of purine metabolism and functions as a material for a conversion that produces superoxide (O2−•) and hydrogen peroxide in the presence of xanthine oxidase[41, 42]. Also, L-arginine is converted by nitic oxide synthase into citrulline and nitric oxide, which induces nitrative and oxidative stress[32, 43]. Furthermore, ROS can be generated from 2-oxoglutarate via 2-oxoglutarate dehydrogenase catalyzation in the Krebs cycle[44–46]. From these perspectives, the decreased levels of these metabolites might be associated with material consumption for ROS generation, which suggests increased oxidative stress in organisms. This assumption was further validated by the elevated plasma MDA level in FM, as numerous studies previously reported[18, 19, 32]. Of note, the expression of altered metabolites and MDA level was significantly increased in FM-PS, which implies that the oxidative status might participate in modulating the soreness phenotype in FM. Further research is needed to clarify the potential relation and underlying mechanisms.
Despites its undetermined etiology, mounting evidence has suggested that FM is associated with aberrant central amplification of nociceptive signaling. Although the investigation of central mechanisms is beyond the scope of this work, our study pointed out a potential link between morbid soreness and central sensitization based on the findings of our current metabolomic profiling and previous translational research . Our prior translational study found that excessive oxidized lipids (e.g., lysophosphatidylcholine) resulting from excessive oxidative stress induces a psychological stress-induced fibromyalgia-like pain by activating acid-sensing ion channel 3 in the muscular tissue, which thus causes central sensitization and results in pain chronification. In this sense, the oxidized metabolites likely function as a nociceptive ligand and subsequently trigger central sensitization to cause FM symptoms. Likewise, this clinical investigation revealed excessive oxidative stress and lipid oxidization in FM individuals, especially in FM-PS. Additionally, it identified a correlative trend between MDA levels and soreness severity. In this content, the development of morbid soreness in FM might also relate to oxidative stress and involve a similar process of central sensitization as the development of pain.
This study has several limitations. First, the sample size may not adequately represent the general population. Also, combining pharmacotherapies of imipramine and pregabalin with individual adjustment were used to relieve symptoms. Ideally, monotherapy would be better for evaluation of therapeutic effects. However, the therapeutic approach of monotherapy is intrinsically limited by its analgesic efficacy or dose-limiting side effects, or both. Additionally, the need for individual drug adjustment would be an intrinsic limitation in the study. Moreover, the observational duration of therapeutic responses for 4 weeks might be not long enough for appropriate assessment. Further studies with a monotherapy design and longer follow-up are needed for better evaluating therapeutic responses and prognosis.