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

TL;DR

SERCA2 in skeletal muscle is now understood as a key regulator of both calcium balance and metabolism, with implications for muscle diseases and metabolic disorders.

Contribution

This review proposes a unified framework for SERCA2's dual role in calcium and metabolism, highlighting gaps in subtype-specific therapeutic strategies.

Findings

SERCA2 integrates calcium signaling, metabolic homeostasis, and ER stress in skeletal muscle.

Dysregulation of SERCA2 is linked to hereditary myopathies, muscle atrophy, and insulin resistance.

Therapeutic strategies targeting SERCA2 show promise for treating systemic diseases.

Abstract

For decades, the sarco/endoplasmic reticulum Ca2+ 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 Ca2+ into the sarcoplasmic reticulum (SR) lumen, thereby sustaining intracellular Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ signaling to systemic metabolism through regulating ER Ca2+ 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.

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