From calcium pump to metabolic hub: emerging genetic phenotypes and metabolic networks of SERCA2 in skeletal muscle

For decades, the sarco/endoplasmic reticulum Ca 2+ ATPase 2 (SERCA2) in skeletal muscle was primarily recognized for its role in orchestrating slow-twitch muscle fiber relaxation—an essential process dependent on its ability to actively sequester cytoplasmic Ca 2+ into the sarcoplasmic reticulum (SR) lumen, thereby sustaining intracellular Ca 2+ homeostasis critical for muscle contraction-relaxation cycles. However, recent genetic and molecular biology studies have expanded the function of SERCA2 to a core hub integrating Ca 2+ signaling, metabolic homeostasis, and endoplasmic reticulum (ER) stress. This novel function is underpinned by a sophisticated multi-layered regulatory network spanning from transcription to post-translational, which ensures that SERCA2 expression and activity dynamically adapt to the dual demands of Ca 2+ homeostasis maintenance and metabolic signaling demands. Dysregulation of this network or mutations in the ATP2A2 gene have been linked to hereditary myopathies, while SERCA2 dysfunction is also a key driver of muscle atrophy and insulin resistance in pathological conditions such as chronic inflammation and obesity. As a metabolic hub, the core mechanism of SERCA2 lies in its role as a critical node connecting local Ca 2+ signaling to systemic metabolism through regulating ER Ca 2+ homeostasis and SERCA2-SLN uncoupling (mediating non-shivering thermogenesis). Therapeutic strategies targeting SERCA2, including small-molecule activators such as CDN1163, AAV9-SERCA2a gene therapy, mimetic peptides, and exercise interventions, have demonstrated potential in treating various systemic diseases by restoring the “calcium pump-metabolism” dual functions of SERCA2. However, the hierarchical regulatory logic linking SERCA2’s calcium-handling and metabolic functions remains fragmented, and subtype-specific therapeutic strategies are undefined. This review synthesizes recent breakthroughs to propose a unified “calcium-metabolism coupling” framework and identifies translational gaps for precision targeting.