Transcriptional profiling of male mouse muscle across aging stages: a gene ontology analysis of the muscle matreotype

In humans, skeletal muscle mass and function progressively decline from the age of 30 years, which corresponds to around 6 months in mice, with a markedly increased rate of decline after the age of 65 years, or 20 months in mice. This process is known as sarcopenia. The mechanisms underlying the transition from adulthood to old age remain unclear. This is partly due to the selection of age groups designated as both control and aging cohorts. Only recently has the extracellular matrix (ECM) been proposed as a hallmark of aging, despite remaining relatively understudied, but the 'aging matreotype,' defined as the composition of the matrisome associated with aging, has yet to be defined. This study aims to identify the optimal age range for comparison with elderly subjects to better understand aging-related biological processes and define the muscle aging matreotype. Over-representation analysis (ORA) and functional class scoring (FCS) were used to compare gene profiling data obtained by microarrays of mouse muscle at 2 (young adult), 11 (mature adult), and 25 (aged) months. The analysis revealed that 82% of gene ontology (GO) terms and differentially expressed genes (DEGs) between 2 and 25 months were also present during maturation (2 to 11 months), but not during aging (11 to 25 months). Aging was characterized by distinct biological processes (BPs), including differentially expressed genes (DEGs) shared with maturation but exhibiting opposite directions of expression. Muscle aging was characterized by structural alterations, synaptic transmission changes, and a decline in ECM and angiogenesis-related BPs, alongside increased apoptotic processes linked to ECM. The study introduced the first transcriptomic 'matreotype' of muscle aging, consisting of 58 genes, 95% of which were downregulated. This study emphasized that to capture aging-specific changes, comparisons should focus on aged (20–22 months) vs. mature adult (around 11 months) male mice. This result should be validated in female mice; and the same applies to the identified stages for studying aging in mice (11 and 25 months). They should be validated in humans, where they correspond approximately to 50 and 70 years of age, respectively. This study introduces the first transcriptional matreotype of mammalian aging and advances our understanding of the matrisome's role. Comparison with proteomics studies highlights the need for integrated transcriptomic and proteomic approaches, with protocols adapted to matrisome analysis.