How Do Muscles Protect Joints in Hemophilia? Integrating Mechanical, Neural, and Endocrine Mechanisms

Abstract: People with hemophilia (PwH) face persistent joint damage risk despite prophylactic factor replacement therapies. Although muscles are recognized as biomechanical stabilizers, their broader protective mechanisms remain poorly understood. This review provides an integrative theoretical framework that examines how muscles protect joints in PwH through three interconnected dimensions: (1) mechanical-via joint stabilization and force absorption; (2) neuromuscular control; and (3) biochemical regulation through exercise-induced myokines (exerkines). Muscle contractions provide joint stabilization and attenuate mechanical impacts via eccentric actions and muscle-tendon buffering, thereby reducing joint loading during daily activities. Neuromuscular control maintains joint stability through coordinated muscle activation, though excessive co-contraction in arthropathy can paradoxically increase joint stress. Critically, the endocrine function of skeletal muscle, producing anti-inflammatory and cartilage-protective exerkines including interleukin-6, irisin, and lubricin (among others), represents an underexplored yet crucial protective mechanism. Physical inactivity and intramuscular fat accumulation impair these protective functions, accelerating joint degeneration. This integrative theoretical perspective offers a comprehensive framework for understanding how muscles protect joints in hemophilia. Understanding these integrated mechanisms is essential for developing targeted rehabilitation strategies and guiding future research to optimize joint health in PwH.