Abstract
Eccentric (ECC) and concentric (CON) contractions induce distinct muscle remodelling patterns that manifest early during exercise training, the causes of which remain unclear. We examined molecular signatures of early contraction mode-specific muscle adaptation via transcriptome-wide network and secretome analyses during 2 weeks of ECC- versus CON-specific (downhill versus uphill running) exercise training (exercise ‘habituation’). Despite habituation attenuating total numbers of exercise-induced genes, functional gene-level profiles of untrained ECC or CON were largely unaltered post-habituation. Network analysis revealed 11 ECC-specific modules, including upregulated extracellular matrix and immune profiles plus downregulated mitochondrial pathways following untrained ECC. Of 3 CON-unique modules, 2 were ribosome-related and downregulated post-habituation. Across training, 376 ECC-specific and 110 CON-specific hub genes were identified, plus 45 predicted transcription factors. Secreted factors were enriched in 3 ECC- and/or CON-responsive modules, with all 3 also being under the predicted transcriptional control of SP1 and KLF4. Of 34 candidate myokine hubs, 1 was also predicted to have elevated expression in skeletal muscle versus other tissues: THBS4, of a secretome-enriched module upregulated after untrained ECC. In conclusion, distinct untrained ECC and CON transcriptional responses are dampened after habituation without substantially shifting molecular functional profiles, providing new mechanistic candidates into contraction-mode specific muscle regulation.
Highlights
Eccentric (ECC) and concentric (CON) contractions induce distinct muscle remodelling patterns that manifest early during exercise training, the causes of which remain unclear
To identify novel molecular drivers of muscles’ early habituation to exercise training, transcriptomics-driven network analysis represents a powerful tool that accounts for the inherent complexity of biological systems, beyond reductionist or traditional differential gene expression analyses alone[19,20,21]
The muscle ‘secretome’ comprises thousands of myokines[27] likely predominantly serving autocrine/paracrine actions that assist muscle remodelling through diverse anabolic, inflammatory, mitochondrial, extracellular matrix (ECM) and angiogenic m echanisms[24,28]
Summary
Eccentric (ECC) and concentric (CON) contractions induce distinct muscle remodelling patterns that manifest early during exercise training, the causes of which remain unclear. Thereafter, post-exercise muscle turnover abates and muscle structural and functional improvements progress comparatively s lowly[4] This biphasic response likely reflects rapid early repair of damaged proteins and gross muscle remodelling events, versus longer-term adaptive processes that become increasingly exercise-mode s pecific[5]. The muscle ‘secretome’ comprises thousands of myokines[27] likely predominantly serving autocrine/paracrine actions that assist muscle remodelling through diverse anabolic, inflammatory, mitochondrial, extracellular matrix (ECM) and angiogenic m echanisms[24,28] This functional diversity appears refined to meet the precise mechanical/metabolic demands of exercise[24,27,28], the muscle secretome might feasibly perform important roles in contraction mode-specific remodelling. Since secreted proteins represent a significant class of efficacious pharmaceutical targets[34], better knowledge of how the intrinsically dense muscle secretome is regulated by contraction mode has important clinical implications, for example the development of exercise mimetics[26,27]
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