Cell biomechanics on muscle atrophy: from intricate mechanisms to therapeutic frontiers.

Background: Muscle atrophy-the decline of skeletal muscle volume and function-is pervasive in chronic disease, aging, and inactivity. As the primary driver of human mobility and metabolic health, skeletal muscle loss diminishes quality of life and increases healthcare burden. Atrophy impairs recovery and prognosis by reducing metabolic capacity, accelerating systemic protein catabolism, and compromising the biomechanical support necessary for movement and respiration. Although core molecular pathways and cellular changes are well characterized, the role of mechanical cues in modulating these mechanisms remains underexplored.

Main findings: Our review reveals five convergent atrophy drivers-mechanical unloading, ECM alterations, mitochondrial dysfunction/oxidative stress, inflammation, and endocrine imbalance-that converge on inhibited mTORC1 signaling, activated FoxO/UPS/autophagy, and impaired satellite-cell function. Quantitative data show that axial stretch preserves PI3K/Akt/mTOR activity, with phosphorylated Akt levels increasing by two- to three-fold and fiber cross-sectional area expanding by 10%-20%; low-intensity compression activates AMPK and autophagy, with AMPK phosphorylation rising by 1.5-fold without triggering excessive protein breakdown; and shear stress enhances VEGF and Nrf2-mediated angiogenesis and antioxidant defenses, doubling VEGF expression and reducing ROS levels by 25% to mitigate neurogenic atrophy. Moreover, stem-cell myogenic differentiation is optimized on 3D biomimetic substrates with stiffness from 11 to 17 kPa under physiological loading, and advances in biomaterials and tissue engineering enable more accurate muscle-tissue models.

Future directions: Translating these biomechanical insights into tailored clinical interventions-combining stretch, compression, and shear modalities with biomaterials, stem-cell technologies, and personalized exercise programs- holds promise for preventing and reversing muscle atrophy across diverse patient populations.