Spatiotemporal multi-omics atlas of the aging neuromuscular junction

The demographic shift toward a global aging population, coupled with rising prevalence of neurodegenerative diseases, poses major public health challenges. Aging is the primary risk factor for most neurodegenerative conditions, making the elucidation of its molecular mechanisms critical for developing effective interventions. Dysfunction of the neuromuscular junction (NMJ), the specialized synapse essential for motor function, is an early hallmark of aging and several neurodegenerative disorders, yet its molecular determinants remain incompletely understood. To shed light on potential common underlying mechanisms, we performed a spatiotemporal multi-omics analysis of the murine NMJ during aging, uncovering several genes showing decoupling between transcript and protein trajectories that may drive the related progressive motor decline. NMJs of soleus (SOL) and extensor digitorum longus (EDL) muscles, differing in fiber composition and vulnerability to aging and disease, displayed distinct spatiotemporal dynamics: fast-twitch EDL, more susceptible to degeneration, exhibited stronger mRNA-protein decoupling than aged slow-twitch SOL or younger SOL and EDL muscles. Elevated expression of miRNAs and RNA-binding proteins in aged EDL highlights the key role of post-transcriptional regulation in NMJ aging. This study provides new insights into the physiopathology of neuromuscular aging and offers a resource for investigating mechanisms shared between aging and neurodegenerative diseases. Additionally, it opens avenues for AI-driven discovery of drug targets and early biomarkers, potentially accelerating the development of therapeutic strategies.