Functional–Structural Uncoupling in Skeletal Muscle Disuse: Divergent Trajectories of Adaptation After Selective Restriction of Mechanical, Neural, and Sensory Inputs

Background: The functional state of skeletal muscle is governed by the interaction of mechanical loading, neural control, and proprioceptive afferentation. Nonetheless, the relative impact of the disruption of these components on muscle function and structure remains insufficiently characterized. Methods: In the present study, we investigated three rat models of muscle disuse and two combined models: hindlimb unloading (n = 40), denervation (D, n = 40), tenotomy (T, n = 40), and the combinations HU + D (n = 8) and HU + T (n = 8), with the cumulative effects evaluated at 7, 14, 35, and 50 days. Functional changes were assessed using electrophysiological methods (M-response recording), and structural changes were evaluated by histological, immunohistochemical, and immunofluorescence analysis. Results: The disuse models elicited significantly distinct trajectories of muscle maladaptation. Hindlimb unloading induced coordinated functional and structural remodeling; denervation provoked early functional decline followed by structural changes; tenotomy largely preserved functional activity despite progressive structural remodeling. The combination of denervation with unloading partially attenuated the negative effects, whereas the combination of unloading and tenotomy led to functional enhancement in some cases. These findings provide insight into the degree of convergence, additivity, and synergy of the disruption of regulatory components and indicate that reduced electrical activity is not invariably associated with synchronous structural degradation, revealing a functional–structural dissociation wherein functional status fails to reflect structural integrity. Conclusions: This observation suggests a previously unrecognized mechanism of maladaptation, which diverges from classical atrophy, broadening our understanding of muscle disuse physiology and offering new perspectives for the development of preventive and therapeutic strategies against atrophic processes.