Laxity Comes with Consequences: Connective Tissue Disorders and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

ME/CFS patients suffer from manifestations of disturbed connective tissue including ligament laxity, hypermobility, craniocervical instability, and orthostatic intolerance due to connective tissue weakness of large vessels, while muscular capillaries show basement membrane thickening. Mast cell overactivity may destabilize connective tissue through chymase and tryptase, activating collagen-degrading metalloproteinases, while cytokines enhance expression. Hypoxia and ROS-mediated inhibition of prolyl hydroxylases impairs crosslinking of newly formed collagen and reduces hypoxia-inducible factor (HIF)-1α degradation. Chronic HIF-1α elevation, in turn, can worsen connective tissue stability by unfavorably altering its composition as recently shown in tendinopathies. ME/CFS associated skeletal muscle dysfunction affecting neck muscles cannot compensate for ligament laxity to stabilize cervical spine but aggravates instability. In skeletal muscle capillaries, elevated HIF-1α may promote extracellular matrix overproduction and basement membrane thickening, impairing capillary perfusion and diffusion, and glycolytic metabolism. The sensitivity of HIF-2α to ROS-mediated degradation may impair angiogenic maturation; the imbalance between HIF-2 α and HIF-1α may permit sustained HIF-1α–driven extracellular matrix production and reduce capillary density. Overall, there seems to be a bidirectional relationship between connective tissue disorders and ME/CFS, whereby connective tissue disorders may predispose individuals to ME/CFS, and ME/CFS, in turn, may exacerbate the underlying connective tissue pathology.