Human skeletal muscle possesses an epigenetic memory of high intensity interval training affecting mitochondrial function
Authors: Pilotto Andrea , Mazzolari Raffaele , Turner Daniel , Gorski Piotr , Crea Emanuela , Zuccarelli Lucrezia , Brocca Lorenza , Pellegrino Maria , Grassi Bruno , Bottinelli Roberto , Sharples Adam , Porcelli Simone 
Published: May 2023

An exposure to hypertrophic stimuli has been shown to lead to faster and larger growth of skeletal muscle when subsequently repeated. Aside from acquired myonuclei permanence, epigenetic modification appears to be involved in the hypertrophic memory at skeletal muscle level. Endurance training interventions increase mitochondrial content and induce mitochondria biogenesis. We aimed to explore whether repeated endurance stimuli can induce changes in mitochondrial function and dynamics due to epigenetic memory. We hypothesized mitochondrial adaptations in response to high-intensity interval training might be influenced by muscle memory at epigenetic level. METHODS: Sixteen subjects (25±5years) underwent to two repeated aerobic training periods (training and retraining) separated by 12 weeks where they were invited to return to their habitual life (detraining). Each training lasted 8 weeks and consisted of a combination between high-intensity interval and sprint interval cycling exercises. At baseline and after training, detraining and retraining peak oxygen consumption (V̇O2peak) and peak power output (Wpeak) were measured. Vastus lateralis muscle samples were collected and mitochondrial respiration (O2 flux by high-resolution respirometry), mitochondrial dynamics, DNA methylation, and gene expression analysis were performed. RESULTS: V̇O2peak and Wpeak improved during both training and retraining (all p<0.001) without differences between the two interventions (p>0.58). Mitochondrial respiration improved in both training and retraining (both p<0.05), but O2 flux changes observed after retraining were greater than those after training (p<0.05). Mitochondrial dynamics were differently affected by training and retraining. Training induced hypomethylation in a large number of differentially methylated positions (DMPs) (14,516). Epigenetic memory profiles were identified in 3,190 DMPs characterized by a hypomethylation state maintained elevated even during detraining, in which mitochondrial respiration returned to baseline levels, and subsequently across retraining. We identified six genes related to muscle function ( ADAM19, INPP5a, MTHFD1L, PDGFB, CAPN2, and SLC16A3) as genes with methylation signature memory that also showed increased expression after retraining, indicating a memory of transcription activity following earlier training. CONCLUSIONS: Physiological adaptions at whole body level seem not to benefit from repeated interventions. However, enhanced responses to the second training were evident at cellular level since mitochondrial function and dynamics were different after retraining. Across repeated interventions, memory profiles were highlighted at epigenetic level characterized by retention of hypomethylation during long-term detraining and retraining period. Methylation and transcriptional memory profiles in genes involved in skeletal muscle metabolic pathways may represent the mechanistic basis of mitochondrial memory. Simone Porcelli was supported by a grant from Sports Medicine Italian Federation (FMSI01092021). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.