Adam Philip Sharples

• Viggars, Mark; Nolan, Andy; Sharples, Adam & Stewart, Claire (2023). Skeletal Muscle Satellite Cell Physiology and Function: Complimentary In Vitro and In Vivo Models and Methods. In Atherton, P.J. & Wilkinson, Daniel J. (Ed.), Neuromuscular Assessments of Form and Function. Humana Press. ISSN 978-1-0716-3314-4. p. 243–274. doi: 10.1007/978-1-0716-3315-1_13.
• Sharples, Adam & Turner, Daniel (2023). Skeletal Muscle Memory. American Journal of Physiology - Cell Physiology. ISSN 0363-6143. 324(6), p. c1274–c1294. doi: 10.1152/ajpcell.00099.2023. Full text in Research Archive Show summary

  Skeletal muscle memory is an exciting phenomenon gaining significant traction across several scientific communities, amongst exercise practitioners and the public. Research has demonstrated that skeletal muscle tissue can be 'primed' by earlier positive encounters with exercise training that can enhance adaptation to later training, even following significant periods of exercise cessation or detraining. This review will describe and discuss the most recent research investigating the underlying mechanisms of skeletal muscle memory: 1) 'cellular' muscle memory and, 2) 'epigenetic' muscle memory as well as the emerging evidence of how these theories may work in synergy. We will discuss both 'positive' and 'negative' muscle memory and highlight the importance of investigating muscle memory for optimising exercise interventions and training programmes as well as the development of therapeutic strategies for counteracting muscle wasting conditions and age-related muscle loss. Finally, important directions emerging in the field will be highlighted to advance the next generation of studies in skeletal muscle memory research into the future.

• McIntosh, Mason C; Sexton, Casey L; Godwin, Joshua S.; Ruple, Bradley A; Michel, J. Max & Plotkin, Daniel L. [Show all 15 contributors for this article] (2023). Different Resistance Exercise Loading Paradigms Similarly Affect Skeletal Muscle Gene Expression Patterns of Myostatin-Related Targets and mTORC1 Signaling Markers. Cells. ISSN 2073-4409. 12(6). doi: 10.3390/cells12060898. Full text in Research Archive Show summary

  Although transcriptome profiling has been used in several resistance training studies, the associated analytical approaches seldom provide in-depth information on individual genes linked to skeletal muscle hypertrophy. Therefore, a secondary analysis was performed herein on a muscle transcriptomic dataset we previously published involving trained college-aged men (n = 11) performing two resistance exercise bouts in a randomized and crossover fashion. The lower-load bout (30 Fail) consisted of 8 sets of lower body exercises to volitional fatigue using 30% one-repetition maximum (1 RM) loads, whereas the higher-load bout (80 Fail) consisted of the same exercises using 80% 1 RM loads. Vastus lateralis muscle biopsies were collected prior to (PRE), 3 h, and 6 h after each exercise bout, and 58 genes associated with skeletal muscle hypertrophy were manually interrogated from our prior microarray data. Select targets were further interrogated for associated protein expression and phosphorylation induced-signaling events. Although none of the 58 gene targets demonstrated significant bout x time interactions, ~57% (32 genes) showed a significant main effect of time from PRE to 3 h (15↑ and 17↓, p < 0.01), and ~26% (17 genes) showed a significant main effect of time from PRE to 6 h (8↑ and 9↓, p < 0.01). Notably, genes associated with the myostatin (9 genes) and mammalian target of rapamycin complex 1 (mTORC1) (9 genes) signaling pathways were most represented. Compared to mTORC1 signaling mRNAs, more MSTN signaling-related mRNAs (7 of 9) were altered post-exercise, regardless of the bout, and RHEB was the only mTORC1-associated mRNA that was upregulated following exercise. Phosphorylated (phospho-) p70S6K (Thr389) (p = 0.001; PRE to 3 h) and follistatin protein levels (p = 0.021; PRE to 6 h) increased post-exercise, regardless of the bout, whereas phospho-AKT (Thr389), phospho-mTOR (Ser2448), and myostatin protein levels remained unaltered. These data continue to suggest that performing resistance exercise to volitional fatigue, regardless of load selection, elicits similar transient mRNA and signaling responses in skeletal muscle. Moreover, these data provide further evidence that the transcriptional regulation of myostatin signaling is an involved mechanism in response to resistance exercise.

• Voisin, Sarah; Seale, Kirsten; Jacques, Macsue; Landen, Shanie; Harvey, Nicholas R & Haupt, Larisa M [Show all 27 contributors for this article] (2023). Exercise is associated with younger methylome and transcriptome profiles in human skeletal muscle. Aging Cell. ISSN 1474-9718. doi: 10.1111/acel.13859. Full text in Research Archive Show summary

  Exercise training prevents age-related decline in muscle function. Targeting epigenetic aging is a promising actionable mechanism and late-life exercise mitigates epigenetic aging in rodent muscle. Whether exercise training can decelerate, or reverse epigenetic aging in humans is unknown. Here, we performed a powerful meta-analysis of the methylome and transcriptome of an unprecedented number of human skeletal muscle samples (n = 3176). We show that: (1) individuals with higher baseline aerobic fitness have younger epigenetic and transcriptomic profiles, (2) exercise training leads to significant shifts of epigenetic and transcriptomic patterns toward a younger profile, and (3) muscle disuse "ages" the transcriptome. Higher fitness levels were associated with attenuated differential methylation and transcription during aging. Furthermore, both epigenetic and transcriptomic profiles shifted toward a younger state after exercise training interventions, while the transcriptome shifted toward an older state after forced muscle disuse. We demonstrate that exercise training targets many of the age-related transcripts and DNA methylation loci to maintain younger methylome and transcriptome profiles, specifically in genes related to muscle structure, metabolism, and mitochondrial function. Our comprehensive analysis will inform future studies aiming to identify the best combination of therapeutics and exercise regimes to optimize longevity.

• Gorski, Piotr Patryk; Turner, Daniel; Iraki, Juma; Morton, James P; Sharples, Adam & Areta, José (2023). Human skeletal muscle methylome after low-carbohydrate energy-balanced exercise. American Journal of Physiology. Endocrinology and Metabolism. ISSN 0193-1849. 324(5), p. E437–E448. doi: 10.1152/ajpendo.00029.2023. Show summary

  We aimed to investigate the human skeletal muscle (SkM) DNA methylome after exercise in low carbohydrate (CHO) energy balance (with high fat) compared with exercise in low-CHO energy deficit (with low fat) conditions. The objective to identify novel epigenetically regulated genes and pathways associated with ‘train-low sleep-low’ paradigms. The sleep-low conditions included 9 males that cycled to deplete muscle glycogen while reaching a set energy expenditure. Post-exercise, low-CHO meals (protein-matched) completely replaced (using high-fat) or only partially replaced (low-fat) the energy expended. The following morning resting baseline biopsies were taken and the participants then undertook 75 minutes of cycling exercise, with skeletal muscle biopsies collected 30 minutes and 3.5 hours post exercise. Discovery of genome-wide DNA methylation was undertaken using Illumina EPIC arrays and targeted gene expression analysis was conducted by RT-qPCR. At baseline participants under energy balance (high fat) demonstrated a predominantly hypermethylated (60%) profile across the genome compared to energy deficit-low fat conditions. However, post exercise performed in energy balance (with high fat) elicited a more prominent hypomethylation signature 30 minutes post-exercise in gene regulatory regions important for transcription (CpG islands within promoter regions) compared with exercise in energy deficit (with low fat) conditions. Such hypomethylation was enriched within pathways related to: IL6-JAK-STAT signalling, metabolic processes, p53 / cell cycle and oxidative / fatty acid metabolism. Hypomethylation within the promoter regions of genes: HDAC2, MECR, IGF2 and c13orf16 were associated with significant increases in gene expression in the post-exercise period in energy balance compared with energy deficit. Furthermore, histone deacetylase, HDAC11 was oppositely regulated at the gene expression level compared with HDAC2, where HDAC11 was hypomethylated yet increased in energy deficit compared with energy balance conditions. Overall, we identify some novel epigenetically regulated genes associated with train-low sleep-low paradigms.

• Lautaoja, Juulia H; Turner, Daniel; Sharples, Adam; Kivelä, Riikka; Pekkal, Satu & Hulmi, Juha J [Show all 7 contributors for this article] (2023). Mimicking exercise in vitro - effects of myotube contractions and mechanical stretch on omics. American Journal of Physiology - Cell Physiology. ISSN 0363-6143. 324(4). doi: 10.1152/ajpcell.00586.2022. Full text in Research Archive Show summary

  The number of studies using skeletal muscle (SkM) cell culture models to study exercise in vitro are rapidly expanding. Progressively, more comprehensive analysis methods, such as different omics approaches including transcriptomics, proteomics and metabolomics have been used to examine the intra- and extracellular molecular responses to exercise mimicking stimuli in cultured myotubes. Among other techniques, exercise-like electrical pulse stimulation (EL-EPS) and mechanical stretch of SkM cells are the two most commonly used methods to mimic exercise in vitro. In this mini-review we focus on these two approaches and their effects on the omics of myotubes and/or cell culture media. Furthermore, besides traditional two-dimensional (2D) methods, the use of three-dimensional (3D) SkM approaches are increasing in the field of in vitro exercise mimicry. Our aim with this mini-review is to provide the reader with an up-to-date overview of the 2D and 3D models and the use of omics approaches to study the molecular response to exercise in vitro.

• Sexton, Casey L; Godwin, Joshua S.; Mcintosh, Mason; Ruple, Bradley A; Osburn, Shelby C & Hollingsworth, Blake [Show all 18 contributors for this article] (2023). Skeletal Muscle DNA Methylation and mRNA Responses to a Bout of Higher versus Lower Load Resistance Exercise in Previously Trained Men. Cells. ISSN 2073-4409. 12(2). doi: 10.3390/cells12020263. Full text in Research Archive Show summary

  We sought to determine the skeletal muscle genome-wide DNA methylation and mRNA responses to one bout of lower load (LL) versus higher load (HL) resistance exercise. Trained college-aged males (n = 11, 23 ± 4 years old, 4 ± 3 years self-reported training) performed LL or HL bouts to failure separated by one week. The HL bout (i.e., 80 Fail) consisted of four sets of back squats and four sets of leg extensions to failure using 80% of participants estimated one-repetition maximum (i.e., est. 1-RM). The LL bout (i.e., 30 Fail) implemented the same paradigm with 30% of est. 1-RM. Vastus lateralis muscle biopsies were collected before, 3 h, and 6 h after each bout. Muscle DNA and RNA were batch-isolated and analyzed using the 850k Illumina MethylationEPIC array and Clariom S mRNA microarray, respectively. Performed repetitions were significantly greater during the 30 Fail versus 80 Fail (p < 0.001), although total training volume (sets × reps × load) was not significantly different between bouts (p = 0.571). Regardless of bout, more CpG site methylation changes were observed at 3 h versus 6 h post exercise (239,951 versus 12,419, respectively; p < 0.01), and nuclear global ten-eleven translocation (TET) activity, but not global DNA methyltransferase activity, increased 3 h and 6 h following exercise regardless of bout. The percentage of genes significantly altered at the mRNA level that demonstrated opposite DNA methylation patterns was greater 3 h versus 6 h following exercise (~75% versus ~15%, respectively). Moreover, high percentages of genes that were up- or downregulated 6 h following exercise also demonstrated significantly inversed DNA methylation patterns across one or more CpG sites 3 h following exercise (65% and 82%, respectively). While 30 Fail decreased DNA methylation across various promoter regions versus 80 Fail, transcriptome-wide mRNA and bioinformatics indicated that gene expression signatures were largely similar between bouts. Bioinformatics overlay of DNA methylation and mRNA expression data indicated that genes related to “Focal adhesion,” “MAPK signaling,” and “PI3K-Akt signaling” were significantly affected at the 3 h and 6 h time points, and again this was regardless of bout. In conclusion, extensive molecular profiling suggests that post-exercise alterations in the skeletal muscle DNA methylome and mRNA transcriptome elicited by LL and HL training bouts to failure are largely similar, and this could be related to equal volumes performed between bouts.

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• Nilsen, Tormod Skogstad; Sæter, Mali; Sarvari, Sebastian; Reinertsen, Kristin Valborg; Johansen, Sara Hassing & Edvardsen, Elisabeth Rustad [Show all 17 contributors for this article] (2023). Effects of Aerobic Exercise on Cardiorespiratory Fitness, Cardiovascular Risk Factors, and Patient-Reported Outcomes in Long-Term Breast Cancer Survivors: Protocol for a Randomized Controlled Trial. JMIR Research Protocols. ISSN 1929-0748. 12. doi: 10.2196/45244. Full text in Research Archive
• Sharples, Adam (2022). Studie om musklenes minne vekker oppsikt. Magne Lund-Hansen (31) «lekte» skadet for å gi forskerne nye svar. [Internet]. Bergens Tidende.
• Sharples, Adam (2022). Musklene kan huske tidligere trening. [Newspaper]. Aftenposten.

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