Silvia Campanario, Mercedes Grima-Terrén, Megan Rommelfanger, Stefania Dell’ Orso, Xuesong Feng, Andrés Cisneros, Ignacio Ramírez-Pardo, Aina Calls-Cobos, Benjamin A. Yang, Kyung Dae Ko, Esther García-Domínguez, Laura Pena-Couso, Grace Chou, Yuewen Zheng, Nasun Hah, Davide Randazzo, Alberto Pérez-Garcia, Tovah E. Markowitz, Jose Milisenda, Iago Pinal‐Fernandez, Andrew Mammen, Mari Carmen Gómez‐Cabrera, Antonio L. Serrano, Eusebio Perdiguero, Vittorio Sartorelli, Joan Isern, Pura Muñoz‐Cánoves
The molecular basis underlying muscle atrophy, as it occurs during disuse or aging, and activity-induced hypertrophy remain poorly understood. A major challenge has been defining the diverse cellular and niche environments within skeletal muscle, which is mostly composed of multinucleated myofibers. Here, we present a single-nucleus and single-cell transcriptomic atlas, coupled with spatial profiling, of mouse limb skeletal muscle under resting conditions and during experimentally induced atrophy or hypertrophy. We identify condition-dependent shifts in muscle-resident cell populations and fiber-type-specific transcriptional responses. We also uncover extensive remodeling of the neuromuscular junction (NMJ), including the emergence of specialized synaptic myonuclei (SynM) and terminal Schwann cells (tSCs) associated with atrophic or hypertrophic states. High-resolution 3D imaging and spatial transcriptomics confirm these changes at the tissue level. Similar NMJ alterations are observed in denervated and exercised human muscle, supporting the translational relevance of this atlas for studying muscle plasticity and identifying therapeutic targets in muscle-related diseases.