This cross-sectional study demonstrated the frequency of sarcopenia using an appropriate definition, incorporating the assessment of both muscle mass and strength. Overall, 42.3% of Japanese patients with CD had a low SMI and 7.7% were diagnosed with sarcopenia. The median age of this CD cohort was 42 years, and 89% of the patients were aged under 60 years. Although we have no data on healthy controls of the same age as this cohort, the frequency of sarcopenia in CD was about the same as that in healthy individuals over the age of 60 years, which was reported to be 8.2% by a recent survey[19].
Although CT is well recognized as the gold standard investigative tool for SMI, it involves radiation exposure and is costly for patients. Moreover, CT information can only be obtained when CT examination is necessary in clinical practice. Most previous reports regarding sarcopenia in CD used CT to estimate SMI and were analyzed retrospectively. The patient groups in those studies were biased towards the collection of patients who required CT examination in their practice. In this study, we showed that the BIA measures of SMI were strongly correlated with CT-based estimates. Thus, BIA is also useful for measuring muscle mass in patients with CD. BIA should be actively used in future prospective studies on sarcopenia in CD because it is non-invasive and convenient.
GDF-15 is a member of the transforming growth factor-beta superfamily (TGF-βs) and is expressed at low concentrations in various organs such as the liver, kidneys, lungs, and other tissues under normal physiological conditions[20, 21]. Elevated inflammatory cytokines, oxidative stress, and hypoxia are known to elevate GDF-15 expression. We demonstrated that GDF-15 negatively correlates with SMI in male patients with CD and can be an indicator of low SMI in multivariate analysis adjusted for age and BMI. The inverse correlation between muscle mass and circulating GDF-15 levels is not specific to CD and has been reported in patients with chronic obstructive pulmonary disease[22], pulmonary arterial hypertension[23], and preoperative cardiovascular disease[24]. Moreover, an inverse association between GDF-15 and MS or function has also been reported in patients with cardiometabolic disease[25] and cancer[26], and in healthy community-dwelling adults[27]. Although the exact mechanisms of serum GDF-15 elevation in CD patients with low SMI remain unknown, some evidence suggests that GDF-15 may promote muscle wasting. It has been reported that glial cell-derived neurotrophic factor receptor alpha-like (GFRAL), the receptor for GDF-15, is present in the brainstem, and that binding of GDF-15 leads to loss of appetite and weight[28–31]. In addition, several reports have suggested a direct catabolic effect of GDF-15 on muscle mass. Patel et al.[22] demonstrated that local overexpression of GDF-15 leads to a reduction in the fiber size of the tibialis anterior muscle in mice. Furthermore, genetic loss of GDF-15 did not affect muscle wasting in transgenic mice characterized by mitochondrial stress-driven skeletal muscle atrophy[32]. In vitro, GDF-15 treatment of C2C12 myotubes elevated the mRNA expression of muscle atrophy-related genes, such as MuRF-1 and Atrogin, and downregulated the expression of muscle microRNAs, such as miR-1, miR-133a, and miR-181a[33]. Further studies are needed to clarify the relationship between circulating GDF-15 levels and muscle wasting in patients with CD and sarcopenia-related outcomes.
Our study has several limitations. First, in our study, sarcopenia was evaluated by MS and SMI. It did not include physical function such as the 6 m walking speed or sit-to-stand test. Therefore, if we evaluated physical function as well as MS, we might have been able to indicate the rate of sarcopenia more accurately in CD patients and analyze between the sarcopenia and non-sarcopenia groups. Second, because our study was a single-center, cross-center study, the causal relationship between GDF-15 and SMI in male patients with CD was unclear. In addition, because there were relatively more males in our study population, it was possible that there was a sex difference in GDF-15 due to bias of sex-specific effects. Therefore, further investigation is needed to clarify the relationship between GDF-15 and SMI in patients with CD. Despite these limitations, to our knowledge, this study is the first to evaluate the association between SMI in CD and GDF-15. We hope that GDF-15 will be a target for indicators of low SMI and therapeutic effects in patients with CD through the accumulation of case data in the future.
In conclusion, 42.3% of Japanese patients with CD had a low SMI and 7.7% were diagnosed with sarcopenia. A low SMI was associated with GDF-15 in male patients with CD. Measurement of GDF-15 may be a predictive biomarker for low SMI, leading to poor prognosis in patients with CD.