CCAAT‐enhancer‐binding protein‐beta expression in vivo is associated with muscle strength

Abstract

Introduction Declining muscle strength is a core feature of aging. Several mechanisms have been postulated, including CCAAT/enhancer-binding protein-beta (C/EBP-β) triggered macrophage-mediated muscle fibre regeneration after micro-injury, evidenced in a mouse model. We aimed to identify in-vivo circulating leukocyte gene expression changes associated with muscle strength in the human adult population. Methods We undertook a genome wide expression microarray screen, using peripheral blood RNA samples from InCHIANTI study participants (ages 30–104 yrs). Logged expression intensities were regressed with muscle strength using models adjusted for multiple confounders. Key results were validated by real-time PCR. The Short Physical Performance Battery score (SPPB) tested walk speed, chair stand and balance. Results CEBPB expression levels were associated with muscle strength (beta coefficient = 0.20560, p=1.03*10−6, false discovery rate q=0.014). The estimated handgrip strength in 70 year old men in the lowest CEBPB expression tertile was 35.2 kg compared to 41.2 kg in the top tertile. CEBPB expression was also associated with hip, knee, ankle and shoulder strength and the SPPB performance score (p=0.018). Near study-wide associations were also noted for TGFB3 (p=3.4*10−5, q=0.12) and CEBPD expression (p=9.67E−5, q=0.18) but not for CEBPA expression. Conclusions We report here a novel finding that raised CEBPB expression in circulating leukocyte derived RNA samples in-vivo is associated with greater muscle strength and better physical performance in humans. This association may be consistent with mouse model evidence of CEBPB triggered muscle repair: if this mechanism is confirmed it may provide a target for intervention to protect and enhance aging muscle.

Genome-Wide Methylated DNA Immunoprecipitation Analysis of Patients with Polycystic Ovary Syndrome

“…CEBPB is important in the regulation of genes involved in immune and inflammatory responses and has been shown to bind to the interleukin (IL) −1 response element in the IL- 6 gene, as well as to regulatory regions of several acute- phase and cytokine genes [33]. Expression of CEBPB in blood leukocytes has been shown to be positively associated with muscle strength in humans, emphasizing the importance of the immune system [34]. In particular, CEBPB is a downstream effector of the luteinizing hormone signaling pathway and thus plays key roles in the luteinizing hormone response of the follicle [35].…”

Changes in the expression of splicing factor transcripts and variations in alternative splicing are associated with lifespan in mice and humans

“…Genes were selected for analysis of alternative splicing in muscle on the basis of potential roles in inflammatory processes relating to muscle remodelling since we have shown in our previous work that these processes are key determinants of muscle strength in older humans (Harries et al ., 2012; Blackwell et al ., 2015). Our gene list included isoforms of the Il1b, Il6, Nfkb1, Stat1 and Tnf genes.…”

Changes in splicing factor expression are associated with advancing age in man

“…Genomics, rather than genetics, may prove a key focus to identify the mechanisms involved in determining successful ageing (Kulminski and Culminskaya, 2013). Accordingly, gene expression analyses have already proven useful in the study of some age-related conditions such as cognitive impairment and decrease in muscle function in the elderly (Pilling et al, 2012; Harries et al, 2012b). …”