Abstract
Mitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible, inexpensive therapeutic intervention that can improve mitochondrial bioenergetics and quality of life. By combining multiple omics techniques with biochemical and in silico normalisation, we removed the bias arising from the training-induced increase in mitochondrial content to unearth an intricate and previously undemonstrated network of differentially prioritised mitochondrial adaptations. We show that changes in hundreds of transcripts, proteins, and lipids are not stoichiometrically linked to the overall increase in mitochondrial content. Our findings suggest enhancing electron flow to oxidative phosphorylation (OXPHOS) is more important to improve ATP generation than increasing the abundance of the OXPHOS machinery, and do not support the hypothesis that training-induced supercomplex formation enhances mitochondrial bioenergetics. Our study provides an analytical approach allowing unbiased and in-depth investigations of training-induced mitochondrial adaptations, challenging our current understanding, and calling for careful reinterpretation of previous findings.
Highlights
Mitochondrial defects are implicated in multiple diseases and aging
The present study utilised the power of multiple omics techniques, and an in silico normalisation strategy eliminating the bias introduced by changes in mitochondrial content, to unearth an intricate and previously undemonstrated network of differentially prioritised mitochondrial adaptations to exercise training in men
A striking and unexpected finding was the early deprioritisation of oxidative phosphorylation (OXPHOS) subunit formation, which indicates that the overall training-induced increase in biogenesis and the proliferation of mitochondria is greater than the increase in specific components of the OXPHOS machinery
Summary
Mitochondrial defects are implicated in multiple diseases and aging. Exercise training is an accessible, inexpensive therapeutic intervention that can improve mitochondrial bioenergetics and quality of life. Many other processes support assembly and maintenance of the OXPHOS complexes, including mitochondrial protein import and assembly pathways, mitochondrial DNA transcription and translation, metabolite carriers, and pathways producing critical cofactors such as coenzyme Q and iron-sulphur proteins (Fe–S)[14]. We employed a 3-phase training intervention, combined with multiple omics techniques (transcriptomics, proteomics, and lipidomics) and a normalisation strategy that removed the bias induced by large alterations in mitochondrial content, to investigate mitochondrial adaptations in human skeletal muscle. Our study provides an analytical approach that expands our fundamental understanding of training-induced mitochondrial biogenesis These findings challenge our current knowledge and call for careful reinterpretation of previous results, while supporting the development of revised hypotheses on how training alters mitochondrial protein content and function, and provide an important resource with implications for both health and disease
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