The Critical Role of Calcium in Skeletal Muscle Function and Its Interaction with Mitochondria and the Endoplasmic Reticulum

Academic Background

Calcium ions (Ca²⁺) are crucial intracellular signaling molecules, particularly in the excitation-contraction coupling (ECC) of skeletal muscle. The contraction of skeletal muscle relies on the release and reuptake of calcium ions from the sarcoplasmic reticulum (SR), a process regulated by various calcium channels and pumps, such as the ryanodine receptor (RYR) and the inositol 1,4,5-trisphosphate receptor (IP3R). Additionally, mitochondria, as the energy factories of cells, influence skeletal muscle function and metabolism by regulating calcium uptake and release.

However, dysregulation of calcium homeostasis can lead to mitochondrial calcium overload, triggering the opening of the mitochondrial permeability transition pore (MPTP), resulting in the release of reactive oxygen species (ROS) and cytochrome c, ultimately causing muscle damage and atrophy. Therefore, studying the regulatory mechanisms of calcium in skeletal muscle, especially the calcium signaling between the endoplasmic reticulum (ER) and mitochondria, is essential for understanding the pathogenesis of muscle diseases and developing preventive strategies.

Source of the Paper

This review paper was co-authored by Xuexin Li, Xin Zhao, Zhengshan Qin, Jie Li, Bowen Sun, and Li Liu from the Department of Anesthesiology at the Affiliated Hospital of Southwest Medical University and the Key Laboratory of Anesthesiology and Critical Care Medicine in Luzhou. The paper was published in 2025 in the journal Cell Communication and Signaling under the title “Regulation of calcium homeostasis in endoplasmic reticulum–mitochondria crosstalk: implications for skeletal muscle atrophy.”

Main Content of the Paper

1. The Critical Role of Calcium in Skeletal Muscle

Calcium ions are not only key regulators of skeletal muscle contraction but also play a vital role in the development, maintenance, and regeneration of muscle cells. The paper elaborates on the mechanisms of calcium release from the ER through RYR and IP3R, as well as the role of the sarcoplasmic reticulum calcium ATPase (SERCA) in calcium reuptake. SERCA pumps calcium ions back into the ER by consuming ATP, allowing the muscle to return to a relaxed state.

2. Calcium Signaling Between the ER and Mitochondria

Calcium signaling between the ER and mitochondria is crucial for maintaining calcium homeostasis. The paper highlights that the close contact between the ER and mitochondria, known as the mitochondria-associated endoplasmic reticulum membrane (MAM), facilitates rapid calcium transfer. RYR and IP3R create localized high-calcium microdomains, promoting rapid calcium uptake by mitochondria, which is essential for mitochondrial energy metabolism and ATP production.

3. Calcium Dysregulation and Muscle Atrophy

Dysregulation of calcium homeostasis can lead to mitochondrial calcium overload, triggering the opening of MPTP, resulting in the release of ROS and cytochrome c, and ultimately causing muscle atrophy. The paper discusses the distinct roles of RYR1 and IP3R in calcium release and their pathological mechanisms in muscle atrophy. For example, RYR1 dysfunction can cause sustained increases in cytoplasmic calcium, leading to mitochondrial calcium overload and cell death.

4. The Role of SERCA in Calcium Homeostasis

SERCA is the most important calcium pump in the SR, responsible for pumping calcium ions from the cytoplasm back into the ER. The paper explores the differential expression of SERCA isoforms (SERCA1, SERCA2, and SERCA3) in skeletal muscle and their impact on calcium dynamics. Additionally, the paper introduces SERCA regulatory proteins, such as phospholamban (PLN) and sarcolipin (SLN), which influence muscle contraction and relaxation by modulating SERCA activity.

5. Regulation of Mitochondrial Calcium Channels

Mitochondria regulate calcium uptake through the voltage-dependent anion channel (VDAC) and the mitochondrial calcium uniporter complex (MCUCx). The paper details the roles of VDAC and MCUCx in calcium transfer and their importance in muscle function. For instance, the absence of MCU reduces mitochondrial calcium uptake, leading to muscle atrophy and impaired motor function.

6. The Role of the Mitochondrial Permeability Transition Pore (MPTP)

The opening of MPTP is a key trigger for apoptosis and necrosis. The paper notes that sustained MPTP opening leads to the collapse of the mitochondrial membrane potential and cell death. In skeletal muscle, MPTP opening is closely associated with muscle atrophy and dysfunction. The paper also discusses the role of MPTP in various muscle diseases, such as amyotrophic lateral sclerosis (ALS) and Duchenne muscular dystrophy (DMD).

Significance and Value of the Paper

This review systematically summarizes the critical role of calcium in skeletal muscle function, particularly the calcium signaling mechanisms between the ER and mitochondria. By detailing the functions of calcium channels and pumps such as RYR, IP3R, SERCA, VDAC, and MCUCx, the paper provides new insights into the pathogenesis of muscle diseases. Furthermore, the paper proposes novel therapeutic strategies targeting calcium signaling pathways, offering potential directions for the prevention and treatment of muscle atrophy and related disorders.

Highlights

1. Comprehensive Exploration of Calcium Homeostasis: The paper thoroughly explains the mechanisms of calcium release, uptake, and transfer in skeletal muscle, revealing the complex interactions between the ER and mitochondria.
2. Pathological Mechanisms of Muscle Atrophy: The paper delves into how calcium dysregulation leads to mitochondrial calcium overload and muscle atrophy, providing new insights into the pathogenesis of muscle diseases.
3. Proposal of Novel Therapeutic Strategies: The paper suggests the possibility of preventing and treating muscle diseases by modulating calcium signaling pathways, offering important directions for future research.

This review not only provides the latest research findings on the role of calcium in skeletal muscle function for the academic community but also serves as a valuable reference for clinicians and researchers, holding significant scientific and practical value.