Mitochondria-associated endoplasmic reticulum membranes in degenerative musculoskeletal disorders: Mechanistic evidence and therapeutic perspectives (Review)

Abstract

Mitochondria-associated endoplasmic reticulum membranes (MAMs) are specialized endoplasmic reticulum (ER) membrane domains at ER-mitochondrial contact sites that coordinate Ca2+ transfer, lipid exchange, mitochondrial quality control and cellular stress responses. In osteoporosis, intervertebral disc degeneration, osteoarthritis and sarcopenia/skeletal muscle atrophy, altered ER-mitochondrial communication has been linked to recurrent disturbances in Ca2+ homeostasis, mitochondrial function, ER stress, inflammatory signaling and cell fate. However, evidence for MAM involvement varies markedly in directness and biological context. This narrative review compares these evidence patterns and their therapeutic implications across degenerative musculoskeletal disorders. Direct structural and causal evidence is most developed in intervertebral disc degeneration and selected osteoarthritis models; osteoporosis is supported mainly by studies of MAM-associated regulators and functional pathways, whereas sarcopenia-specific mechanisms remain largely informed by aging muscle and related experimental models. The direction and consequences of contact remodeling also vary with cell type, metabolic state and disease stage, arguing against a uniform gain- or loss-of-contact model. Interventions targeting contact-site regulators or MAM-related Ca2+ and mitochondrial pathways have shown preclinical benefit, but MAM-specific target engagement and human validation remain limited. Progress will require paired structural and functional assessment together with validation in clinically characterized human tissues and patient-derived systems.