Parkin is a critical player in the effects of caffeine over mitochondrial quality control pathways during skeletal muscle regeneration in mice

• Published in: Acta Physiologica 2024-03, Vol.240 (3), p.e14111-n/a
• Main Authors: Esteca, M. V., Divino, I. A., Vieira da Silva, A. L., Severino, M. B., Braga, R. R., Ropelle, E. R., Simabuco, F. M., Baptista, I. L.
• Format: Article
• Language: English
• Subjects: AMPK; Animals; Caffeine; Caffeine - pharmacology; Cell differentiation; Mice; Mice, Inbred C57BL; Mitochondria; Mitochondrial DNA; mitochondrial respiration; Mitophagy; muscle recovery; Muscle, Skeletal - metabolism; Musculoskeletal system; Myoblasts; Myotubes; Parkin protein; Phosphorylation; Protein biosynthesis; Protein synthesis; Proteins; Quality control; Regeneration; Satellite cells; Skeletal muscle; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism
• ISSN: 1748-1708; 1748-1716; 1748-1716
• DOI: 10.1111/apha.14111

Aim This study aimed to investigate the effects of caffeine on pathways associated with mitochondrial quality control and mitochondrial capacity during skeletal muscle regeneration, focusing on the role of Parkin, a key protein involved in mitophagy. Methods We used in vitro C2C12 myoblast during differentiation with and without caffeine in the medium, and we evaluated several markers of mitochondrial quality control pathways and myotube growth. In vivo experiments, we used C57BL/6J (WT) and Parkintm1Shn lineage (Parkin−/−) mice and injured tibial anterior muscle. The mice regenerated TA muscle for 3, 10, and 21 days with or without caffeine ingestion. TA muscle was used to analyze the protein content of several markers of mitochondrial quality pathways, muscle satellite cell differentiation, and protein synthesis. Furthermore, it analyzed mtDNA, mitochondrial respiration, and myofiber growth. Results C2C12 differentiation experiments showed that caffeine decreased Parkin content, potentially leading to increased DRP1 and PGC‐1α content and altered mitochondrial population, thereby enhancing growth capacity. Using Parkin−/− mice, we found that caffeine intake during the regenerative process induces an increase in AMPKα phosphorylation and PGC‐1α and TFAM content, changes that were partly Parkin‐dependent. In addition, the absence of Parkin potentiates the ergogenic effect of caffeine by increasing mitochondrial capacity and myotube growth. Those effects are related to increased ATF4 content and activation of protein synthesis pathways, such as increased 4E‐BP1 phosphorylation. Conclusion These findings demonstrate that caffeine ingestion changes mitochondrial quality control during skeletal muscle regeneration, and Parkin is a central player in those mechanisms.