Chronic obstructive pulmonary disease (COPD) and sarcopenia, present significant clinical and socioeconomic challenges within geriatric populations [1, 2, 3]. COPD is the third leading cause of death worldwide, with the estimated global financial impact of International Dollars (INT$) 4.3 trillion between 2020 and 2050 [3]. At the population level, a study on the economic burden of sarcopenia assessed its direct healthcare costs in the United States at $18.5 billion for the year 2000 [1].

COPD is a complex and heterogeneous condition characterized by persistent inflammation and various extrapulmonary manifestations [4, 5, 6, 7, 8]. Patients with COPD often exhibit comorbidities, including cardiovascular disease, metabolic dysfunctions, osteoporosis, muscular disorders, cachexia, and mental health conditions, all of which detrimentally affect patient outcomes [5, 7, 8]. Sarcopenia, characterized by age-related reductions in skeletal muscle mass, strength, and function, frequently coexists with COPD [9, 10]. The extrapulmonary manifestations of COPD can severely influence performance by reducing physical activity and diminishing muscle mass and strength, thereby significantly compromising the quality of life [11, 12, 13]. These physical factors are strongly associated with the onset and progression of sarcopenia [14, 15]. A recent systematic meta-analysis reported a higher prevalence of sarcopenia (27.5%) among COPD patients [16]. Furthermore, sarcopenia is related to a range of adverse outcomes, including extended hospitalization, increased risk of fractures, acute exacerbations, falls, disability, and mortality—serving as a strong prognostic indicator for worse disease progression [11, 15]. While observational studies consistently suggest a close association between COPD and sarcopenia, the presence of confounding variables limits the capability to ascertain a direct causal relationship. Therefore, more effective approaches are required to determine their causal relationship, informing targeted management and intervention strategies for these interrelated conditions.

Given the current research-based evidence, we hypothesized that sarcopenia has a causal relationship with both COPD and hospitalization risk, and we tested this assumption using a Mendelian randomization (MR) approach. MR analysis includes genetic variants as instrumental variables (IVs) to evaluate causal links between exposures and outcomes, effectively minimizing the risk of confounding factors and reversing causation [17]. Despite the clinical significance causal links between COPD and sarcopenia, limited studies have explored this association using MR approaches. To date, no randomized controlled trials (RCTs) have been performed to evaluate the bidirectional interactions between these two interrelated conditions. Therefore, we conducted a bi-directional two-sample MR analysis to assess causal associations between sarcopenia, COPD, and hospitalization risk, employing appendicular lean mass (ALM), hand grip strength (HGS), usual walking pace (UWP), and moderate-to-vigorous physical activity (MVPA).

This study utilized an univariable two-sample bi-directional MR to systematically elucidate the causal links between sarcopenia-associated traits, including ALM, HGS, UWP, and MVPA and the risk of COPD and hospitalization. The findings revealed a significant negative causal relationship, demonstrating that genetically determined reduction in ALM, HGS, UWP, and MVPA increases the risk of COPD and hospitalization. Furthermore, these associations were successfully validated through replication analyses. Although the primary MR analysis suggested a negative correlation between COPD and diminished UWP, this finding was not replicated in the MR validation analysis. To our knowledge, this is the first bi-directional MR study to comprehensively evaluate the causal link between sarcopenia-associated traits and COPD and hospitalization risk, while accounting for potential confounders.

Previous observational studies have indicated that sarcopenia elevates the risk of COPD. A prospective, population-based cohort investigation undertaken in Rotterdam, The Netherlands, revealed a higher incidence of COPD among sarcopenic (26.9%) and pre-sarcopenic (29.1%) patients relative to the nonsarcopenic (13.4%) individuals [34]. Similarly, another study involving 469,830 participants from the UK Biobank indicated that gait-muscle group individuals had a 4.16-fold higher risk of COPD than those with the normal physical ability (HR: 4.16, 95% CI: 2.59–6.70), followed by those with severe sarcopenia (HR: 3.85, 95% CI: 2.24–6.62). Sarcopenia in this study was described based on the combination of 3 indicators of physical function: muscle mass, grip strength, and gait speed [35]. The Invecchiare in Chianti (InCHIANTI, Aging in the Chianti Region) study, which longitudinally analyzed 538 participants, revealed that sarcopenia was correlated with a higher hospitalization rate (60% vs. 48%, p = 0.087). Even after adjusting for potential confounders, sarcopenia remained notably associated with hospital admission (HR: 1.57; 95% CI: 1.03–2.41) [36]. Furthermore, a retrospective analysis of 174,808 COPD patients in the United States in 2011 reported associations between muscle loss and increased morbidity and mortality, with sarcopenic patients experiencing longer hospital stays and higher associated costs compared to non-sarcopenic patients. These observations are consistent with our results, indicating a causal association between sarcopenia and increased risks of COPD and hospitalization. According to EWGSOP definitions, the diagnosis of sarcopenia requires meeting both low grip strength and low muscle mass, with severe sarcopenia characterized by reduced gait speed. Our findings demonstrate the substantial negative causal association between ALM, MVPA, UWP, and HGS with COPD and hospitalization, supporting the conclusion that sarcopenia increases the risk of COPD and related hospitalizations.

Several systematic reviews and meta-analyses of prior observational studies have suggested an association between COPD and an elevated risk of sarcopenia [11, 16, 37]. While epidemiological surveys across varied populations have shown different prevalence rates of sarcopenia among COPD patients, meta-analyses consistently underscore its frequent co-occurrence. However, in our study, no genetic evidence supports the causal impact of COPD and hospitalization on sarcopenia-related traits. While the primary MR analysis suggested a negative correlation between COPD and diminished UWP, this finding was not replicated in the MR validation analysis. Given our study’s rigor in applying FDR correction for multiple comparisons and considering the complex interrelations between COPD and sarcopenia, these results warrant cautious interpretation. Further investigation is needed to assess these associations more thoroughly in future studies. Sarcopenia-related traits, like ALM and HGS, serve as key predictors of muscle mass, and low muscle mass has been linked to poor pulmonary function [38, 39]. A cross-sectional study analyzing 452 COPD patients reported a significant association between reduced lean mass and elevated risk of emphysema, a crucial phenotype of COPD [40]. Meanwhile, UWP and MVPA are used as a measure of physical activity performance levels. Evidence suggests that prolonged sedentary behavior may lead to an inadequate physical exercise, adversely affecting both muscle and lung functions, thereby increasing the risk of COPD [41, 42, 43]. Conversely, higher physical activity has been associated with a lower risk of COPD, likely through preserving lean mass and reducing oxidative stress and minimizing chronic airway inflammation [44, 45, 46, 47, 48]. Moreover, MVPA has been reported to have positive effects on lung function at the population level [49]. Taken together, these interrelated clinical factors provided a considerable basis for the observed association between sarcopenia and the higher incidence of COPD and hospitalization risk.

The occurrence of comorbidities in sarcopenia and COPD involves a multidimensional biological interaction, with systemic inflammation playing a crucial role. Increased levels of serum pro-inflammatory factors, such as C-reactive protein (CRP), Interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-$\alpha$) have been consistently found in COPD patients, where they accelerate myofibrillar protein degradation by upregulating the expression of muscle-specific ubiquitin ligases (MuRF1 and MAFbx) through activation of the Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-$\kappa$B) pathway [50, 51]. Oxidative stress may be another key mechanism, manifested by the excessive accumulation of reactive oxygen species (ROS) in COPD patients. ROS not only impairs mitochondrial function and muscle energy metabolism but also synergizes with inflammatory factors to activate inflammatory signaling pathways such as p38 Mitogen-Activated Protein Kinase (p38 MAPK), forming a vicious circle that aggravates muscle atrophy and dysfunction [52, 53]. Additionally, an imbalance in actin regulation further elucidates the link between sarcopenia and COPD. For example, irisin promotes muscle growth and is usually elevated during physical activity but is reduced in patients with COPD, whereas levels of myostatin, an inhibitor of muscle regeneration, are elevated [54]. This imbalance skews muscle metabolism towards catabolic processes, accelerating the onset of sarcopenia. However, despite these promising insights, the specific pathophysiological mechanisms linking sarcopenia and COPD remain poorly understood.

The growing understanding of the biological mechanisms linking sarcopenia and COPD carries significant therapeutic implications. Evidence suggested that managing sarcopenia in COPD patients is both feasible and effective through well-structured exercise programs supported by a balanced nutritional intake. Various other events, such as resistance training, aerobic exercise, and pulmonary rehabilitation have been found to improve muscle strength and endurance, while adequate protein intake, vitamin D, omega-3s, and calories help preserve muscle mass [54, 55, 56, 57]. Given the possible negative causal association observed in our study, combining these interventions may maximize therapeutic outcomes and reduce the risk of sarcopenia-related COPD exacerbation and hospitalization. These evidence-based strategies, based on the latest research findings, provide clinicians with a crucial framework for public health decision-making aimed at managing sarcopenia to reduce its impact on COPD patients.

The current study has several significant strengths. Firstly, it comprehensively evaluated critical features related to muscle quality, muscle strength, and physical performance, while also including hospitalization phenotypes alongside COPD, thereby enhancing the rigor and representativeness of the study. Secondly, MR studies, often considered natural randomized controlled trials, offer more robust findings than traditional observational studies. Furthermore, we executed extensive validation and sensitivity analyses to confirm the result’s robustness, especially when heterogeneity was observed: a random-effects IVW was used to minimize its effect. Finally, we effectively excluded confounding factors such as air pollution, smoking, alcohol consumption, body mass index (BMI), and blood lipid levels, mitigating potential biases.

Nonetheless, we acknowledge certain limitations in our study. Specifically, our study population was limited to participants of European ancestry. Due to significant genetic differentiation between East Asian and European populations, with about 12% of SNPs exhibiting significant Fixation Index (FST) differences (indicative of considerable allele frequency differences), which may limit the generalizability of the results across different ethnic groups [58]. Additionally, stratification based on common factors such as age and sex were unattainable due to constraints in the available summarized GWAS data. Moreover, the causal links between COPD-related hospitalization and sarcopenia-associated traits could not be validated due to a lack of relevant data. Lastly, there are inherent limitations in the MR approach. However, the use of MR-PRESSO helped to reduce the risk of horizontal pleiotropy by identifying and excluding outlier SNPs, its validity relies on the assumption of linearity and cannot entirely exclude the possibility of residual pleiotropy arising from nonlinear causation or epigenetic modulation [30].

It should also be noted that, in the partial MR analysis, we employed a relatively lenient threshold (p 1 $\times$ 10^-5) for IV selection due to the limited number of variants meeting the more stringent threshold (p 5 $\times$ 10^-8). Although all selected SNPs had F-values $>$10, thus meeting the threshold to reduce weak instrumental bias, and pleiotropic SNPs were excluded, the potential for weak instrument bias remains. Additionally, individual leave-one-out plots demonstrated that there are potentially influential SNPs driving the causal link between exposures and outcomes, suggesting the possibility of unrecognized pleiotropy in some SNPs that could influence the stability of our findings. In future studies, using a Polygenic Risk Score, colocalization analyses to prioritize causal SNPs, or the integration of proteomic MR to enhance biological specificity could further validate findings in this area.

In conclusion, this study indicates a causal association between sarcopenia and elevated risks of COPD and hospitalization, providing reliable genetic evidence for the adverse impacts of sarcopenia on both outcomes within the European population. These findings underscore the clinical and public health importance of targeting sarcopenia improvement as a promising strategy to reduce the incidence of COPD and minimize hospitalization risk.

$\bullet$ This study employed a bi-directional two-sample MR approach to systematically investigate causal relationships between sarcopenia-related traits (ALM, HGS, UWP, MVPA) and both COPD and hospitalization risk, overcoming limitations of observational studies.

$\bullet$ Genetically predicted lower ALM, reduced HGS, slower UWP, and decreased MVPA significantly increased the risk of COPD and COPD-related hospitalization, supporting a unidirectional causal effect of sarcopenia on COPD exacerbation.

$\bullet$ The findings highlight that intervention targeting muscle preservation (e.g., resistance training, nutritional support) may reduce COPD incidence and hospitalization burden, offering practical strategies for mitigating age-related cardiopulmonary morbidity.

$\bullet$ Robust sensitivity analyses (MR-PRESSO, leave-one-out), FDR correction, and replication using independent UK Biobank dataset strengthened causal inferences, with minimal pleiotropy or heterogeneity observed (Cochran’s Q p $>$ 0.05 for most traits).

$\bullet$ While emphasizing sarcopenia’s causal role, this study underscores the need for multi-ethnic cohorts, mechanistic exploration of muscle-lung interactions (e.g., oxidative stress pathways), and trials testing targeted sarcopenia therapies in COPD populations.

All data generated or analyzed during this study are available from the corresponding author on reasonable request.

ZK designed the study. SN acquired the data. ZK and SN interpreted the data. SN and XL drafted the manuscript. XL was involved in the analysis and interpretation of data in the clinical part of medicine. XL focused on participating in the writing of the medical clinical section. All authors contributed to the critical revision of the manuscript for important intellectual content. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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This research received no external funding.

The authors declare no conflict of interest.

Supplementary material associated with this article can be found, in the online version, at https://doi.org/10.31083/BJHM50164.