Sulforaphane Mimics Contractile Activity-Induced Mitochondrial Adaptations in Muscle

Research Background

Mitochondria are central regulators of skeletal muscle health, acting as the cell’s power plants. The function and quality of mitochondria directly impact muscle health. Exercise has been widely proven to be an effective means of enhancing mitochondrial function by activating mitochondrial quality control processes (such as mitochondrial biogenesis and mitochondrial dynamics), improving mitochondrial function, and reducing the accumulation of reactive oxygen species (ROS). However, there is currently a lack of pharmaceutical interventions that can mimic exercise-induced mitochondrial adaptations. Therefore, researchers have begun exploring the potential of natural compounds in improving mitochondrial function.

Sulforaphane (SFN) is a natural compound found in cruciferous vegetables (such as broccoli and cauliflower) and is known for its strong antioxidant effects through the activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, the role of SFN in muscle health has not been fully studied. This study aims to explore whether SFN can mimic exercise-induced mitochondrial adaptations and further investigate the interaction between SFN and chronic contractile activity (CCA).

Source of the Paper

This paper was authored by Sabrina Champsi and David A. Hood from the Muscle Health Research Centre at York University in Canada. It was first published on December 14, 2024, in the American Journal of Physiology-Cell Physiology, with the DOI: 10.1152/ajpcell.00669.2024.

Research Workflow and Results

1. Study Design and Experimental Model

The study used the C2C12 mouse skeletal muscle cell line as an experimental model, differentiating them into myotubes to simulate skeletal muscle cells. The experiment was divided into several steps, primarily investigating the effects of SFN on mitochondrial function, antioxidant capacity, and biogenesis, as well as its interaction with chronic contractile activity (CCA).

1.1 SFN Treatment and Mitochondrial Function Assessment

Researchers first exposed C2C12 myotubes to SFN (10 μM) treatment for 24 and 48 hours, followed by assessing mitochondrial function using Western blotting, flow cytometry, and Seahorse mitochondrial respiration assays. The results showed that SFN significantly increased the expression of mitochondrial transcription factor A (TFAM) and mitofusin 2 (MFN2), indicating that SFN promoted mitochondrial biogenesis and fusion. Additionally, SFN significantly enhanced mitochondrial respiratory capacity, including basal respiration, ATP-linked respiration, and maximal respiration.

1.2 Antioxidant Capacity Assessment

To evaluate the antioxidant effects of SFN, researchers measured ROS levels in cells and mitochondria and the expression of antioxidant enzymes. The results showed that SFN significantly reduced ROS accumulation in both cells and mitochondria and upregulated the expression of various antioxidant enzymes (e.g., glutathione reductase, catalase). This indicates that SFN enhanced cellular antioxidant capacity by activating the Nrf-2 pathway.

1.3 Mitochondrial Dynamics and Morphology Analysis

Through confocal microscopy, researchers found that SFN treatment significantly increased mitochondrial branch length and the number of connection points, indicating that SFN promoted the connectivity of the mitochondrial network. Moreover, SFN reduced the expression of the mitochondrial fission-related protein DRP1 (Dynamin-Related Protein 1), further supporting its role in mitochondrial fusion.

2. Interaction Between SFN and Chronic Contractile Activity

To investigate whether SFN could mimic or enhance exercise-induced mitochondrial adaptations, researchers exposed C2C12 myotubes to electrically stimulated chronic contractile activity (CCA) and administered SFN treatment during the recovery period. The results showed that combined SFN and CCA treatment did not significantly enhance mitochondrial biogenesis or antioxidant capacity, suggesting that the signaling pathways activated by SFN are similar to those induced by CCA. This implies that SFN may simulate the positive effects of exercise on mitochondria through similar molecular mechanisms.

3. Molecular Mechanism Study

To further elucidate the mechanism of action of SFN, researchers evaluated the nuclear translocation of Nrf-2 and the expression of its downstream target genes. The results showed that SFN significantly promoted the nuclear translocation of Nrf-2 and upregulated multiple genes related to mitochondrial biogenesis and antioxidant capacity. Additionally, SFN enhanced the promoter activity and nuclear translocation of PGC-1α (Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha), indicating that SFN regulates mitochondrial biogenesis through the activation of PGC-1α.

Conclusions and Significance

This study demonstrates that SFN can mimic exercise-induced mitochondrial adaptations by activating the Nrf-2 pathway, including enhancing mitochondrial biogenesis, improving mitochondrial dynamics, and boosting antioxidant capacity. These findings provide scientific evidence for developing SFN-based therapeutic strategies, particularly in improving skeletal muscle mitochondrial function. Furthermore, the study reveals the similarity between SFN and exercise in terms of molecular mechanisms, laying the groundwork for further research on the application of SFN in sports medicine and muscle disease treatment.

Research Highlights

1. SFN Mimics Exercise Effects: SFN mimics the positive effects of exercise on mitochondrial biogenesis, dynamics, and antioxidant capacity by activating the Nrf-2 pathway.
2. Comprehensive Mitochondrial Function Assessment: The study comprehensively assessed the effects of SFN on mitochondrial function using methods such as Western blotting, flow cytometry, Seahorse respiration assays, and confocal microscopy.
3. Elucidation of Molecular Mechanisms: The study revealed that SFN regulates mitochondrial biogenesis and antioxidant capacity by activating Nrf-2 and PGC-1α.

Other Valuable Information

The study also found that SFN treatment significantly increased the expression of lysosome-related proteins (such as TFE3 and Cathepsin B), indicating that SFN may promote mitochondrial quality control by enhancing lysosomal function. This provides new directions for future research on the role of SFN in cellular autophagy and mitochondrial renewal.

This study not only reveals the potential of SFN in improving mitochondrial function but also provides important scientific evidence for developing muscle health intervention strategies based on natural compounds.