Cummings, S. R. | Search bioRxiv

bioRxiv2026

MicroRNA regulatory targets of VO2peak in older adult participants of the Study of Muscle Mobility and Aging (SOMMA)

Skeletal muscle aging (sarcopenia) is associated with reduced peak oxygen consumption (VO peak) during exercise, a key determinant of physical function and overall health. However, the molecular mechanisms linking muscle aging to low VO peak remain poorly understood. We aimed to identify miRNA signatures and miRNA-gene regulatory networks associated with VO peak in older adults. Using small RNA and mRNA sequencing, we analyzed skeletal muscle from 72 SOMMA participants (70-79 years old) with low or high VO peak (n = 18/group) and from 36 participants spanning the full VO peak spectrum. Differential expression was assessed using LIMMA, with pathway and network analyses performed using Ingenuity Pathway Analysis (IPA) and Weighted Gene Co-expression Network Analysis (WGCNA). We detected 1,408 miRNAs and 16,210 genes; among these, 14 miRNAs and 2,018 genes were differentially expressed (FDR < 0.05). The 14 miRNAs regulated 142 genes, and expression of 10 miRNAs inversely correlated with 50 genes enriched in mitochondrial, sirtuin-1, and nitric oxide signaling pathways. Regression analyses identified 21 miRNAs and 1,744 genes significantly correlated with VO peak after adjusting for age and sex. WGCNA revealed 10 co-expression modules associated with VO peak, with the cyan module showing the strongest correlation and enrichment for nitric oxide signaling genes. These findings highlight novel miRNA-mediated molecular pathways potentially contributing to low VO peak and skeletal muscle aging in older adults. Future studies will further investigate these miRNA-gene interactions to uncover therapeutic targets for preserving muscle function with age.

molecular biology↗

bioRxiv2025

Poorer physical function is associated with elevated spatial entropy in the aging brain network landscape

Life is a constant struggle against disorder. As we age, our ability to maintain internal order declines. In the healthy human brain, order is observable in the form of functionally segregated brain network communities that exhibit spatial consistency. These communities associate with distinct cognitive and physical functions. When mapped into the brain, they form a functional "landscape". We assessed the spatial disorder of these landscapes in older adults with a wide range of mobility using a modified version of Shannon entropy. We found that compared to younger adults, older adults had significantly higher entropy in the sensorimotor cortex, basal ganglia, hippocampus, thalamus, and occipital lobe. Higher entropy in many of these regions was associated with worse physical function and higher body mass index in older adults. Findings suggest that spatial entropy in brain network landscapes may be a marker of declining physical function. Modifiable factors, such as losing excess weight, may help to ameliorate aging-related brain entropy increases in regions such as the sensorimotor cortex, which may in turn help to preserve physical function in older adults.

neuroscience↗