The current assessment of disease progression in SCA3 involves neurological examinations, such as SARA, for evaluating ataxia. NfL [11] and BMI [21] have established themselves as reliable predictors of SCA3, and our research uncovered a robust relationship between HGS and SARA, even after adjusting for gender and age. The increased strength of HGS can predict higher BMI and lower plasma levels of NfL. Additionally, a higher HGS/BMI ratio indicated lower scores in the SARA evaluation. Moreover, our study demonstrated that patients with SCA3 exhibited significantly lower HGS compared to healthy controls. This study represents the first instance where HGS or the HGS/BMI ratio has independently predicted the disease severity of SCA3, including all eight subscores of SARA. HGS can serve as an easily accessible tool to estimate the disease status of SCA3 in a clinical setting, even when considering the gene loading of SCA3-CAG repeat expansion.
HGS is a widely used measure of muscular strength, but various factors can influence its accuracy. HGS in patients with SCA3 may relate to myopathy, neuropathy or other comorbidity. Our study revealed a significant inverse correlation between HGS and disease severity, even after controlling for common factors. Various conditions, including arthritis, tendinitis, and major vascular or neurological disorders, can affect grip strength. Other factors, such as sex, age, handedness, and nutritional status, also impact HGS [24]. Participants with severe comorbidities, such as stroke, cancer, heart failure, or kidney failure, were excluded, and the absence of arthritis or tendinitis was screened to ensure the accuracy of our study. Handedness was determined according to the standard protocol for using a hand dynamometer [25], while sex and age were considered during statistical analysis.
Accordingly, recent literature revealed a report investigating grip strength in transgenic SCA3 135Q mice without mentioning the pathogenesis that contributes to the reduction of grip strength [26]. In the present study, we found a similar result in SCA3 84Q mice with weak grip strength compared with WT during the late disease stage. To account for the potential confounding effect of decreased body weight in SCA3 84Q mice at 18 months, we adjusted for body weight and still detected weaker grip strength in SCA3 mice compared to WT mice. Our previous studies have also demonstrated a decrease in the ratios of muscle mass and body weight in the quadriceps, gastrocnemius, tibialis, extensor digitorum longus, and soleus muscles compared to WT mice. The cross-sectional area of muscle fibers was found to be reduced in SCA3 84Q mice [27]. Atrophic signaling involving Akt/Forkhead box-O and myosin heavy chain (MyHC) expressions were implicated in these findings, indicating the existence of sarcopenia or muscle disease [28, 29]. Specifically, our study revealed a significant decrease in phosphorylated AKT and the muscle cell differentiation marker, MyHC, in SCA3 84Q mice compared to WT mice which indicated the possible muscular pathogenesis involved in the disease of SCA3 [27].
Muscle weakness is a common feature in patients with SCA3, and recent studies indicate that myopathic origin may contribute to distal muscle weakness in these individuals [30]. Further, evidence indicates a potential association between SCA3 and sarcopenia, as patients with SCA3 display lower muscle strength and lean mass than healthy controls [31]. Therefore, the muscle atrophy pathway may be related to the lower HGS observed in patients with SCA3 who have sarcopenia. Our study revealed that sarcopenia-related BMI and HGS could provide valuable insights into the clinical progression of patients with SCA3. A declining BMI signifies deterioration in the condition of patients with SCA3 and may indicate the possible occurrence of comorbidity with sarcopenia. Another report suggests that hyperkinesia may lead to increased energy expenditure, while dysphagia results in decreased nutrition intake, both potentially contributing to a body composition resembling sarcopenia [31]. The Foundation for the National Institutes of Health Biomarkers Consortium Sarcopenia Project also recommends grip strength measurements, such as HGS and HGS/BMI ratio, as non-Dual-energy X-ray absorptiometry approaches to identify sarcopenic patients among the elderly [32]. Our study revealed that HGS not only helps assess the clinical severity of SCA3 but is also significantly related to BMI. HGS can be regarded as a valuable tool for evaluating the progression of SCA3 patients with sarcopenia.
Therefore, further investigation into the possible mechanism of decreased HGS, including peripheral neuropathy, such as electromyography, nerve conduction studies, or even muscle biopsy, should be considered as the next step. In the future, we will conduct long-term longitudinal observations to examine the relationship between HGS and disease progression and expand our sample size to include more SCA3 patients and normal subjects.