Gene polymorphisms associated with heterogeneity and senescence characteristics of sarcopenia in chronic obstructive pulmonary disease

Abstract

Background Sarcopenia, or loss of skeletal muscle mass and decreased contractile strength, contributes to morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD). The severity of sarcopenia in COPD is variable, and there are limited data to explain phenotype heterogeneity. Others have shown that COPD patients with sarcopenia have several hallmarks of cellular senescence, a potential mechanism of primary (age‐related) sarcopenia. We tested if genetic contributors explain the variability in sarcopenic phenotype and accelerated senescence in COPD. Methods To identify gene variants [single nucleotide polymorphisms (SNPs)] associated with sarcopenia in COPD, we performed a genome‐wide association study (GWAS) of fat free mass index (FFMI) in 32 426 non‐Hispanic White (NHW) UK Biobank participants with COPD. Several SNPs within the fat mass and obesity‐associated (FTO) gene were associated with sarcopenia that were validated in an independent COPDGene cohort (n = 3656). Leucocyte telomere length quantified in the UK Biobank cohort was used as a marker of senescence. Experimental validation was done by genetic depletion of FTO in murine skeletal myotubes exposed to prolonged intermittent hypoxia or chronic hypoxia because hypoxia contributes to sarcopenia in COPD. Molecular biomarkers for senescence were also quantified with FTO depletion in murine myotubes. Results Multiple SNPs located in the FTO gene were associated with sarcopenia in addition to novel SNPs both within and in proximity to the gene AC090771.2, which transcribes long non‐coding RNA (lncRNA). To replicate our findings, we performed a GWAS of FFMI in NHW subjects from COPDGene. The SNP most significantly associated with FFMI was on chromosome (chr) 16, rs1558902A > T in the FTO gene (β = 0.151, SE = 0.021, P = 1.40 × 10−12 for UK Biobank |β= 0.220, SE = 0.041, P = 9.99 × 10−8 for COPDGene) and chr 18 SNP rs11664369C > T nearest to the AC090771.2 gene (β = 0.129, SE = 0.024, P = 4.64 × 10−8 for UK Biobank |β = 0.203, SE = 0.045, P = 6.38 × 10−6 for COPDGene). Lower handgrip strength, a measure of muscle strength, but not FFMI was associated with reduced telomere length in the UK Biobank. Experimentally, in vitro knockdown of FTO lowered myotube diameter and induced a senescence‐associated molecular phenotype, which was worsened by prolonged intermittent hypoxia and chronic hypoxia. Conclusions Genetic polymorphisms of FTO and AC090771.2 were associated with sarcopenia in COPD in independent cohorts. Knockdown of FTO in murine myotubes caused a molecular phenotype consistent with senescence that was exacerbated by hypoxia, a common condition in COPD. Genetic variation may interact with hypoxia and contribute to variable severity of sarcopenia and skeletal muscle molecular senescence phenotype in COPD.

Combining Bulk and Single-Cell RNA Sequencing Data to Identify RNA methylation and Autophagy-Related Signatures in Patients with Chronic Obstructive Pulmonary Disease

“…Animal experiments further showed upregulation of FTO in mice with LPS-induced ARDS(47). Similarly, emerging evidence has linked SNPs in the FTO gene to sarcopenia in COPD patients (50).…”

Muscle loss phenotype in COPD is associated with adverse outcomes in the UK Biobank

“…Our definition of COPD included a pre-bronchodilator FEV1/FVC ratio < 0.7, given that post-bronchodilator spirometry is not available in the UK Biobank. While there is potential to over-diagnose COPD when using pre-bronchodilator testing [ 34 ], pre-bronchodilator testing has been previously used in UK Biobank studies of COPD [ 35 , 36 ] and other large scale epidemiologic studies including the Copenhagen Heart Study [ 12 ]. Even though the UK Biobank provides the age at which COPD was diagnosed by a physician, the true duration of COPD diagnosis may be longer.…”

“…Our preclinical studies in skeletal muscle cells using an in vitro model of prolonged intermittent hypoxia demonstrate physiologic perturbations consistent with muscle loss in COPD [ 45 ]. We have also identified single nucleotide polymorphisms in the UK Biobank associated with low muscle mass in COPD patients, allowing for further translation of these preclinical data to human studies [ 35 ]. Additional studies are needed to determine the molecular mechanisms of muscle loss and dysfunction in COPD to develop new and innovative therapeutic strategies for COPD patients with MLP.…”

Functional SNPs in SYISL promoter significantly affect muscle fiber density and muscle traits in pigs

“…The SNPs of lncRNAs can affect the function of lncRNAs and play an important role in cancer (Feng Hua et 2018;Shah et al, 2018;Tian et al, Yan et al, 2021), muscle growth (Al-Tobasei et al, 2017;Yang et al, 2021;Zhou et al, 2018), muscle fiber girth and body weight (Attaway et al, 2023).…”

“…The SNPs of lncRNAs can affect the function of lncRNAs and play an important role in cancer (Feng et al., 2020; Hua et al., 2018; Shah et al., 2018; Tian et al., 2020; Yan et al., 2021), muscle growth (Al‐Tobasei et al., 2017; Yang et al., 2021; Zhou et al., 2018), muscle fiber girth and body weight (Attaway et al., 2023). Therefore, the identification of SNPs within lncRNAs is of important significance for functional variation in non‐coding regions.…”