Matrisome, innervation and oxidative metabolism affected in older compared with younger males with similar physical activity

Abstract

Background Due to the interaction between skeletal muscle ageing and lifestyle factors, it is often challenging to attribute the decline in muscle mass and quality to either changes in lifestyle or to advancing age itself. Because many of the physiological factors affecting muscle mass and quality are modulated by physical activity and physical activity declines with age, the aim of this study is to better understand the effects of early ageing on muscle function by comparing a population of healthy older and young males with similar physical activity patterns. Methods Eighteen older (69 ± 2.0 years) and 20 young (22 ± 2.0 years) males were recruited based on similar self-reported physical activity, which was verified using accelerometry measurements. Gene expression profiles of vastus lateralis biopsies obtained by RNA sequencing were compared, and key results were validated using quantitative polymerase chain reaction and western blot. Results Total physical activity energy expenditure was similar between the young and old group (404 ± 215 vs. 411 ± 189 kcal/day, P = 0.11). Three thousand seven hundred ninety-seven differentially expressed coding genes (DEGs) were identified (adjusted P-value cut-off of <0.05), of which 1891 were higher and 1906 were lower expressed in the older muscle. The matrisome, innervation and inflammation were the main upregulated processes, and oxidative metabolism was the main downregulated process in old compared with young muscle. Lower protein levels of mitochondrial transcription factor A (TFAM, P = 0.030) and mitochondrial respiratory Complexes IV and II (P = 0.011 and P = 0.0009, respectively) were observed, whereas a trend was observed for Complex I (P = 0.062), in older compared with young muscle. Protein expression of Complexes I and IV was significantly correlated to mitochondrial capacity in the vastus lateralis as measured in vivo (P = 0.017, R 2 = 0.42 and P = 0.030, R 2 = 0.36). A trend for higher muscle-specific receptor kinase (MUSK) protein levels in the older group was observed (P = 0.08). Conclusions There are clear differences in the transcriptome signatures of the vastus lateralis muscle of healthy older and young males with similar physical activity levels, including significant differences at the protein level. By disentangling physical activity and ageing, we appoint early skeletal muscle ageing processes that occur despite similar physical activity. Improved understanding of these processes will be key to design targeted anti-ageing therapies.

Sex differences in skeletal muscle-aging trajectory: same processes, but with a different ranking

“…However, the populations used in the meta-analysis were very heterogeneous (e.g., trained and sedentary participants were included, and both young and adult participants were used as control groups), and the exact comparisons that were done were poorly described. Furthermore, it could be argued that mRNA levels encoding OXPHOS subunits do not necessarily translate into oxidative function; however, this is unlikely in the light of previously reported significant correlations between OXPHOS subunit levels and in vivo mitochondrial capacity in old and young male participants [22].…”

“…Well-studied drivers of age-related loss of muscle mass and strength include a decreased mitochondrial content or function [22,23]. One electron microscopy study measured mitochondrial content and found that intermyofibrillar mitochondrial size was primarily decreased in old females and not in old males [18].…”

Age‐related changes in human skeletal muscle transcriptome and proteome are more affected by chronic inflammation and physical inactivity than primary aging

“…Several studies attempted to identify molecular changes associated with "healthy" aging in human skeletal muscle, considering primary aging with minimal contribution of physical impairment and chronic diseases. For this, different muscle molecular parameters were compared between physically active and sedentary elderly people (Hinkley et al, 2023;Lanza et al, 2008) or between young (sedentary) and older people with a comparable level of physical activity/performance (physically active) (Lagerwaard et al, 2021;Lanza et al, 2008;Murgia et al, 2017;Ubaida-Mohien et al, 2019).…”

Preserved stem cell content and innervation profile of elderly human skeletal muscle with lifelong recreational exercise

“…2020; Lagerwaard et al . 2021; Monti et al . 2021) have availed ourselves of this to indirectly investigate myofibre innervation status in human muscle tissue.…”

“…For example, a strong upregulation of the acetylcholine receptors (AChR), normally confined to the NMJ, is evident along the length of the myofibre upon denervation (Merlie et al 1984). We (Karlsen et al 2019(Karlsen et al , 2020Soendenbroe et al 2019Soendenbroe et al , 2020 and others (Gigliotti et al 2015;Baehr et al 2016;Kelly et al 2018;Sonjak et al 2019;Daou et al 2020;Skoglund et al 2020;Lagerwaard et al 2021;Monti et al 2021) have availed ourselves of this to indirectly investigate myofibre innervation status in human muscle tissue.…”