Objective: Lipotoxic hepatocyte injury is a primary event in non-alcoholic steatohepatitis (NASH), but the mechanisms of lipotoxicity are not fully defined. Sphingolipids and free cholesterol (FC) mediate hepatocyte injury, but their link in NASH has not been explored. We examined the role of free cholesterol and sphingomyelin synthases (SMSs) that generate sphingomyelin (SM) and diacylglycerol (DAG) in hepatocyte pyroptosis, a specific form of programmed cell death associated with inflammasome activation, and NASH. Design: Wild-type C57BL/6J mice were fed a high fat and high cholesterol diet (HFHCD) to induce NASH. Hepatic SMS1 and SMS2 expressions were examined in various mouse models including HFHCD-fed mice and patients with NASH. Pyroptosis was estimated by the generation of the gasdermin-D N-terminal fragment. NASH susceptibility and pyroptosis were examined following knockdown of SMS1, protein kinase Cδ (PKCδ), or the NLR family CARD domain-containing protein 4 (NLRC4). Results: HFHCD increased the hepatic levels of SM and DAG while decreasing the level of phosphatidylcholine. Hepatic expression of Sms1 but not Sms2 was higher in mouse models and patients with NASH. FC in hepatocytes induced Sms1 expression, and Sms1 knockdown prevented HFHCD-induced NASH. DAG produced by SMS1 activated PKCδ and NLRC4 inflammasome to induce hepatocyte pyroptosis. Depletion of Nlrc4 prevented hepatocyte pyroptosis and the development of NASH. Conditioned media from pyroptotic hepatocytes activated the NOD-like receptor family pyrin domain containing 3 inflammasome (NLRP3) in Kupffer cells, but Nlrp3 knockout mice were not protected against HFHCD-induced hepatocyte pyroptosis. Conclusion: SMS1 mediates hepatocyte pyroptosis through a novel DAG-PKCδ-NLRC4 axis and holds promise as a therapeutic target for NASH.

Though bioelectrical impedance analysis (BIA) is a favorable tool for assessing body composition to estimate nutritional status and physical fitness, such as sarcopenia, there are accuracy issues. Hence, high-frequency (HF) BIA equipment uses an additional frequency of 2 and 3 MHz and has been developed as a commercial model. However, there are no studies validating the accuracy and safety of HF-BIA. Therefore, this study aims to assess the validity of HF-BIA in analyzing body composition relative to dual-energy X-ray absorptiometry (DEXA). Appendicular lean mass (ALM), fat-free mass (FFM), and percentage of body fat (PBF) were assessed by HF-BIA and DEXA in 109 individuals; 50.5% (n = 55) were males. The average age and body mass index (BMI) were 43.4 ± 14.7 years and 25.5 ± 6.7 in males and 44.9 ± 14.1 years and 24.0 ± 6.4 in females, respectively. The HF-BIA results showed a high correlation with the DEXA results for assessing ALM (standard coefficient beta (β) ≥ 0.95), FFM (β ≥ 0.98, coefficient of determinations (R²) ≥ 0.95), and PBF (β ≥ 0.94, R² ≥ 0.89). Body composition measured by HF-BIA demonstrated good agreement with DEXA in Korean adults.

Breathlessness shares aging mechanisms of frailty and sarcopenia. Are frailty and sarcopenia associated with breathlessness itself? We analyzed data from a population-based, prospective cohort study of 780 community-dwelling older adults. Breathlessness was defined using the modified Medical Research Council Dyspnea Scale (≥2 points) and the Chronic Obstructive Pulmonary Disease Assessment Test (≥10 points). Frailty was defined by frailty index (FI), frailty phenotype, and FRAIL questionnaire. Sarcopenia was defined by the Asian Working Group for Sarcopenia 2019. Sarcopenia phenotype score quantifies the number of criteria met. The associations of frailty and sarcopenia with breathlessness was evaluated by logistic regression analyses. Adjusted odds ratio (aOR) were calculated, accounting for age, sex, chronic airway disease, smoking status, body mass index, lung functions, socioeconomic status (living alone, income, education), comorbid conditions (hypertension, diabetes, malignancy, myocardial infarction, heart failure), and other geriatric contributors (cognitive dysfunction, depression, malnutrition, polypharmacy, fall history in the past year). Institutionalization-free survival was compared by log-rank test. The prevalence of frailty is higher in the breathlessness group compared to non-breathlessness group (42.6% vs. 10.5% by FI, 26.1% vs. 8.9% by frailty phenotype, and 23.0% vs. 4.2% by FRAIL) and sarcopenia (38.3% vs. 26.9%), with P < 0.01 for all comparisons. The multivariable logistic regression analyses showed that frailty (FI [aOR: 9.29], FRAIL questionnaire [aOR: 5.21], and frailty phenotype [aOR: 3.09]) and sarcopenia phenotype score (score 2 [aOR: 2.00] and score 3 [aOR: 2.04] compared to score 0) were associated with breathlessness. The cumulative incidence of institutionalization-free survival was higher in the breathlessness group than counterparts (P = 0.02). The findings suggest that frailty and sarcopenia strongly contribute to breathlessness in community-dwelling older adults. Measuring sarcopenia and frailty in older adults may offer opportunities to prevent age-related breathlessness.

Background: Functional sarcopenia is characterized by decreased physical performance and grip strength despite preserved muscle mass. The effectiveness of a program combining exercise and nutritional support—known interventions for individuals with low muscle mass—was evaluated for its impact on older adults with functional sarcopenia. Methods: An unblinded, parallel-group randomized controlled trial was conducted in a public medical center in a rural Korean community. Eligible older adults with functional sarcopenia were randomized into either the intervention group, receiving a 12-week program of group exercises and nutritional support, or the control group, receiving education on lifestyle management. Outcomes measured included changes in gait speed, grip strength, physical performance, and quality of life indices. Results: The study enrolled 42 participants, with 21 allocated to each group. Compared with the control group, the intervention group showed significant improvements in the primary outcome of gait speed (mean change (m/s) 0.24 vs 0.00, p< 0.001) and secondary outcomes, such as Short Physical Performance Battery scores, grip strength, and quality of life. No significant adverse events were reported. Conclusion: The 12-week exercise and nutritional intervention significantly enhanced physical performance, grip strength, and quality of life among community-dwelling older adults with functional sarcopenia. This suggests that strategies commonly recommended for sarcopenia, including exercise and nutritional support, are also beneficial for individuals with functional sarcopenia, indicating the potential for broader application of such interventions.

Sarcopenia, which is characterized by an age-related decline in muscle mass and function, poses significant challenges to geriatric care. Its definition has evolved from muscle-specific criteria to include muscle mass, muscle function, and physical performance, recognizing sarcopenia as a physical frailty. Sarcopenia is associated with adverse outcomes, including mortality, falls, fractures, cognitive decline, and admission to long-term care facilities. Neuromechanical factors, protein-energy balance, and muscle protein synthesis-breakdown mechanisms contribute to its pathophysiology. The identification of sarcopenia involves screening tests and a comprehensive assessment of muscle mass, strength, and physical function. Clinical approaches aligned with the principles of comprehensive geriatric assessment prioritize patient-centered care. This assessment aids in identifying issues related to activities of daily living, cognition, mood, nutrition, and social support, alongside other aspects. The general approach to factors underlying muscle loss and functional decline in patients with sarcopenia includes managing chronic diseases and evaluating administered medications, with interventions including exercise and nutrition, as well as evolving pharmacological options. Ongoing research targeting pathways, such as myostatin-activin and exercise mimetics, holds promise for pharmacological interventions. In summary, sarcopenia requires a multifaceted approach, acknowledging its complex etiology and tailoring interventions to individual patient needs.