Biology subjects

Lindholm, M. E.

Publications and source records attributed to Lindholm, M. E..

16 recordsLinked to original sources

bioRxiv2026

Integrative Multi-omics Analysis of the Human Skeletal Muscle Response to Endurance or Resistance Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)

The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to systematically characterize the molecular basis of the health benefits of exercise. Here, we present the integrative, multi-omics response of human skeletal muscle to acute endurance (EE) and resistance (RE) exercise. Distinct temporal responses were observed, with changes in ATAC-seq, phosphoproteome, and metabolome occurring before changes in the transcriptome and proteome. These distinct temporal multi-omic dynamics were used to identify transcriptional regulatory hubs converging around MEF2A and NFIC regulation of autophagy, angiogenesis and metabolism. Further, early RE-specific phosphoproteome signatures counteracted epigenetic modifications and downregulated transcripts involved in protein turnover. Additional findings include suppression of HIPK2/3 kinase signatures linked to the acute exercise regulation of sarcomeric proteins TTN, NEB, ANKRD2 and LMOD2. Our data demonstrate distinct temporal regulation across the multi-omic landscape of human skeletal muscle, with EE and RE eliciting common and unique molecular signatures.

systems biology↗

bioRxiv2026

Blood Biochemical Responses to Acute Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC)

Exercise benefits numerous organ systems and tissues, however limited knowledge exists about its underlying molecular pathways. Identifying the exercise-induced biochemical changes that occur in the circulation may provide further insights into how exercise confers systemic health changes. Here, we perform large-scale plasma proteomic, metabolomic, and whole blood transcriptional profiling in sedentary human participants undergoing acute endurance exercise (EE), resistance exercise (RE), or a non-exercise control (CON) in up to 7 timepoints over a 24 hour period. We observe 7066 transcript, 189 protein, and 448 metabolite changes in response to EE or RE compared to CON. Our analyses reveal numerous shared biochemical responses between EE and RE modes, but also differences in immune cell responses, lipid metabolism, and pathways reflective of tissue repair and angiogenesis. Taken together, our findings highlight novel temporal and exercise mode-specific blood-based molecular responses to acute exercise, and provide a new resource for the scientific community.

systems biology↗

bioRxiv2026

Multi-Omic, Multi-Tissue Responses to Acute Exercise in Sedentary Adults: Findings from the Molecular Transducers of Physical Activity Consortium

Regular physical activity represents one of the greatest mechanisms for maintaining human health, yet the underlying molecular transducers of these benefits remain incompletely understood. Multi-omic assays now provide new opportunities to study the coordinated molecular responses of body tissues to different exercise modalities. The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to address this need by creating a molecular map of the response to physical activity. Described here is the first human cohort of MoTrPAC: sedentary adults enrolled prior to study suspension during the COVID-19 pandemic (N=175) randomized to either endurance or resistance exercise, or non-exercise control. From these participants, we detail their global acute molecular response in skeletal muscle, adipose tissue, and blood, integrated at multiple levels: tissue, exercise modality, timepoint, and omic category. These analyses characterize key molecular pathways, identify central regulators, and implicate novel candidate exerkines in mediating multi-organ exercise effects.

systems biology↗

bioRxiv2025

Temporal Multi-Omic Analysis Uncovers Sex-Biased Molecular Programs Underlying Skeletal Muscle Adaptation to Endurance Training

BackgroundExercise training is known to benefit health and reduce disease risk. While skeletal muscle adaptations are fundamental to many of the health benefits of exercise training, the common and sex-specific molecular regulators that mediate these adaptations remain to be fully elucidated. MethodsTo this end, we leveraged skeletal muscle multi-omics data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), where 6 month-old male and female rats endurance trained for 1, 2, 4, or 8 weeks. Our objective was to identify shared and sex-specific multi-omic molecular responses to endurance training in skeletal muscle, and relate them to phenotypic adaptations. ResultsWe identified largely sexually-conserved transcriptomic and proteomic pathway enrichments in the gastrocnemius, which correlated with skeletal muscle responses from a published exercise study in humans. We uncovered sex-consistent post-translational modifications, including decreased oxidation of MYH2 and deacetylation of the {beta}-oxidation enzyme HADHA. Pathway enrichment analyses revealed sex-specific remodeling across the acetylome, redox proteome, and phosphoproteome; females decreased mitochondrial protein cysteine oxidation and increased mitochondrial cristae proteins, indicative of enhanced redox buffering and mitochondrial efficiency. Despite decreases in cysteine oxidation of key mitochondrial proteins, females displayed increases in the cysteine oxidation of proteins involved in glucose catabolism relative to males after 8 weeks of training, suggestive of sex-biased subcellular reactive oxygen species generation. Males demonstrated earlier induction of mitochondrial transcripts and predicted activation of mTOR. Although the increase in mitochondrial protein abundance was more modest in males, there was greater oxidation of mitochondrial proteins in response to training compared to females. ConclusionsThis work shows a large portion of the adaptive response to endurance training in skeletal muscle is shared between females and males, while there are distinct and nuanced sex-specific adaptations that are evident, particularly at the level of post-translational regulation.

physiology↗

bioRxiv2025

Transcriptomic Profiling of scWAT Reveals Reduced Lipid-Associated Macrophage Signatures in Long-Term Endurance- and Resistance-Trained Athletes

Regular exercise training is associated with systemic and tissue-specific performance and health benefits, yet long-term molecular adaptations in subcutaneous abdominal white adipose tissue (scWAT) remain unclear. We analyzed the resting scWAT transcriptome of 89 adults (35-50 years) who were long-term (>15 years) endurance- or strength-trained, or untrained. Long-term training was linked to enrichment of ribosomal, mitochondrial, and aerobic metabolism-related pathways, while immune-related pathways were enriched in untrained individuals. A distinct sex dimorphic scWAT was identified: untrained females exhibited a more metabolically favorable, trained-like transcriptomic profile, and untrained males an untrained-like profile. In trained males, the inflammatory gene signature was lower than in untrained males. We also identified 11 genes specific to lipid-associated macrophages with lower expression in trained individuals, particularly in all endurance-trained individuals and strength-trained females. These findings highlight sex-specific, exercise-induced adaptations in scWAT relevant to metabolic health, and underscore the importance of including both sexes in scWAT research.

physiology↗

bioRxiv2025

The Long Non-coding RNA Landscape of Endurance Exercise Training

Long non-coding RNAs (lncRNAs) regulate multiple cellular processes. However, knowledge of the responses and regulatory functions of lncRNAs in physical exercise and training remains limited. As part of the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we conducted a comprehensive analysis of lncRNA expression patterns in 18 tissues after an 8-week progressive endurance training program in rats. The lncRNA expression pattern was largely tissue-specific. In total, 759 unique lncRNAs were found to be differentially expressed across all tissues, generally displaying lower abundance, shorter transcript length, and reduced GC content compared with protein-coding genes. The most pronounced changes were observed in white and brown adipose tissues, the hypothalamus, and the adrenal gland. In the two skeletal muscle tissues investigated, only two lncRNAs were commonly differentially expressed. White and brown adipose tissues revealed a correlation between upregulated differentially expressed lncRNAs and coding genes associated with immune regulation. We identified substantial sex differences in the lncRNA regulatory landscape in response to exercise training. This comprehensive tissue-specific characterization of exercise-responsive lncRNAs opens new avenues for understanding exercise as molecular medicine and may inform the development of lncRNA-targeted therapeutics that harness the beneficial effects of exercise.

physiology↗

bioRxiv2025

Endurance exercise drives temporal and sexual dimorphic multi-omic adaptations in liver metabolism-Findings from MoTrPAC.

The mechanisms by which exercise modulate liver metabolism, a central regulator of systemic metabolism, are poorly understood. Leveraging data from MoTrPAC, we analyzed liver adaptations across 1, 2, 4, and 8 weeks of exercise in male and female rats using multi-omic approaches. Female livers displayed a progressive increase in oxidative phosphorylation (OXPHOS) complexes (at the protein level), while male livers showed an increase in acetylation of OXPHOS, TCA cycle, and fatty acid oxidation enzymes. Exercise also enhanced liver cholesterol and bile acid synthesis, reducing liver lipid metabolites in males after 8 weeks of exercise. Male rats had higher fecal cholesterol and cholic acid levels, indicating a sex-specific mechanism of lipid excretion with exercise. Moreover, 8 weeks of training reduced markers related to hepatic stellate cell activation and fibrosis in both sexes. This study highlights the sexual dimorphic and temporal molecular signatures by which exercise modulates liver metabolism to provide hepatoprotective effects.

physiology↗

bioRxiv2025

Sexually distinct multi omic responses to progressive endurance exercise training in the rat lung. Findings from MoTrPAC

Despite the lungs being essential for ventilation and aerobic exercise capacity, conventionally the lungs are not thought to adapt to exercise training. Endurance exercise is key to pulmonary rehabilitation programs, which also displays sex-specific differences in therapeutic efficacy. Given the molecular underpinnings of sex-specific lung adaptations to endurance exercise are uncharacterized, we used a multi-omics approach to study sex differences in the lungs of 6-month-old Fischer 344 rats in response to an 8 week progressive endurance treadmill training protocol. This was accomplished by reannotating publicly accessible data from the Molecular Transducers of Physical Activity Consortium (MoTrPAC) and integrating newly-analyzed acetylome data to assess multi-omic sex differences in sedentary and progressively trained states. Female rats displayed enrichment in immune-related features and pathways at the transcriptome and proteome level that were maintained with training. Conversely, in the male rat lung there was an overall decrease in immune pathways following 8 weeks of training. Sexually conserved responses to training included increased enrichment in transcriptomic pathways related to type I alveoli and proteomic pathways related to cilia, and decreased mitochondrial protein acetylation. In both sexes, features known to be enriched in lung diseases were attenuated with training. Together our findings provide novel insight into sex specific responses to endurance exercise training in the rat lung and may offer translational insight into sex-specific differences in lung disease pathogenesis and treatment.

physiology↗

bioRxiv2023

Sexual dimorphism and the multi-omic response to exercise training in rat subcutaneous white adipose tissue

Subcutaneous white adipose tissue (scWAT) is a dynamic storage and secretory organ that regulates systemic homeostasis, yet the impact of endurance exercise training and sex on its molecular landscape has not been fully established. Utilizing an integrative multi-omics approach with data generated by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), we identified profound sexual dimorphism in the dynamic response of rat scWAT to endurance exercise training. Despite similar cardiorespiratory improvements, only male rats reduced whole-body adiposity, scWAT adipocyte size, and total scWAT triglyceride abundance with training. Multi-omic analyses of adipose tissue integrated with phenotypic measures identified sex-specific training responses including enrichment of mTOR signaling in females, while males displayed enhanced mitochondrial ribosome biogenesis and oxidative metabolism. Overall, this study reinforces our understanding that sex impacts scWAT biology and provides a rich resource to interrogate responses of scWAT to endurance training.

molecular biology↗

bioRxiv2023

The mitochondrial multi-omic response to exercise training across tissues

Mitochondria are adaptable organelles with diverse cellular functions critical to whole-body metabolic homeostasis. While chronic endurance exercise training is known to alter mitochondrial activity, these adaptations have not yet been systematically characterized. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) mapped the longitudinal, multi-omic changes in mitochondrial analytes across 19 tissues in male and female rats endurance trained for 1, 2, 4 or 8 weeks. Training elicited substantial changes in the adrenal gland, brown adipose, colon, heart and skeletal muscle, while we detected mild responses in the brain, lung, small intestine and testes. The colon response was characterized by non-linear dynamics that resulted in upregulation of mitochondrial function that was more prominent in females. Brown adipose and adrenal tissues were characterized by substantial downregulation of mitochondrial pathways. Training induced a previously unrecognized robust upregulation of mitochondrial protein abundance and acetylation in the liver, and a concomitant shift in lipid metabolism. The striated muscles demonstrated a highly coordinated response to increase oxidative capacity, with the majority of changes occurring in protein abundance and post-translational modifications. We identified exercise upregulated networks that are downregulated in human type 2 diabetes and liver cirrhosis. In both cases HSD17B10, a central dehydrogenase in multiple metabolic pathways and mitochondrial tRNA maturation, was the main hub. In summary, we provide a multi-omic, cross-tissue atlas of the mitochondrial response to training and identify candidates for prevention of disease-associated mitochondrial dysfunction.

molecular biology↗

bioRxiv2023

Multiomic identification of key transcriptional regulatory programs during endurance exercise training

Transcription factors (TFs) play a key role in regulating gene expression. We conducted an integrated analysis of chromatin accessibility, DNA methylation, mRNA expression, protein abundance and phosphorylation across eight tissues in fifty rats of equally represented sexes following endurance exercise training (EET) to identify coordinated epigenomic and transcriptional changes and determine key TFs involved. We uncovered tissue-specific EET associated changes and TF motif enrichment across differentially expressed genes (DEGs), accessible regions (DARs), and methylated regions (DMRs). We discovered distinct routes of EET-induced regulation through either epigenomic alterations providing better access for TFs to affect target genes, or via changes in TF expression or activity enabling target gene responses. We identified TF motifs enriched among correlated epigenomic and transcriptomic alterations, DEGs correlated with exercise-related phenotypic and cell type composition changes, and EET-induced activity changes of TFs whose target genes are enriched for DEGs. This analysis elucidates the unique gene regulatory mechanisms mediating diverse transcriptional responses to EET across tissues.

genomics↗

bioRxiv2022

Exercise rejuvenates the skeletal muscle methylome and transcriptome in humans

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 = 3,176). 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 towards 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 towards a younger state after exercise training interventions, while the transcriptome shifted towards 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.

molecular biology↗

bioRxiv2022

Temporal dynamics of the multi-omic response to endurance exercise training across tissues

Regular exercise promotes whole-body health and prevents disease, yet the underlying molecular mechanisms throughout a whole organism are incompletely understood. Here, the Molecular Transducers of Physical Activity Consortium (MoTrPAC) profiled the temporal transcriptome, proteome, metabolome, lipidome, phosphoproteome, acetylproteome, ubiquitylproteome, epigenome, and immunome in whole blood, plasma, and 18 solid tissues in Rattus norvegicus over 8 weeks of endurance exercise training. The resulting data compendium encompasses 9466 assays across 19 tissues, 25 molecular platforms, and 4 training time points in young adult male and female rats. We identified thousands of shared and tissue- and sex-specific molecular alterations. Temporal multi-omic and multi-tissue analyses demonstrated distinct patterns of tissue remodeling, with widespread regulation of immune, metabolism, heat shock stress response, and mitochondrial pathways. These patterns provide biological insights into the adaptive responses to endurance training over time. For example, exercise training induced heart remodeling via altered activity of the Mef2 family of transcription factors and tyrosine kinases. Translational analyses revealed changes that are consistent with human endurance training data and negatively correlated with disease, including increased phospholipids and decreased triacylglycerols in the liver. Sex differences in training adaptation were widespread, including those in the brain, adrenal gland, lung, and adipose tissue. Integrative analyses generated novel hypotheses of disease relevance, including candidate mechanisms that link training adaptation to non-alcoholic fatty liver disease, inflammatory bowel disease, cardiovascular health, and tissue injury and recovery. The data and analysis results presented in this study will serve as valuable resources for the broader community and are provided in an easily accessible public repository (https://motrpac-data.org/). HighlightsO_LIMulti-tissue resource identifies 35,439 analytes regulated by endurance exercise training at 5% FDR across 211 combinations of tissues and molecular platforms. C_LIO_LIInterpretation of systemic and tissue-specific molecular adaptations produced hypotheses to help describe the health benefits induced by exercise. C_LIO_LIRobust sex-specific responses to endurance exercise training are observed across multiple organs at the molecular level. C_LIO_LIDeep multi-omic profiling of six tissues defines regulatory signals for tissue adaptation to endurance exercise training. C_LIO_LIAll data are available in a public repository, and processed data, analysis results, and code to reproduce major analyses are additionally available in convenient R packages. C_LI

molecular biology↗

bioRxiv2020

Mono- and bi-allelic protein truncating variants in alpha-actinin 2 cause cardiomyopathy through distinct mechanisms

Alpha-actinin 2 (ACTN2) anchors actin within cardiac sarcomeres. The mechanisms linking ACTN2 mutations to myocardial disease phenotypes are unknown. Here, we characterize patients with novel ACTN2 mutations to reveal insights into the physiological function of ACTN2. Patient-derived iPSC-cardiomyocytes harboring ACTN2 protein-truncating variants were hypertrophic, displayed sarcomeric structural disarray, impaired contractility, and aberrant Ca2+-signaling. In heterozygous indel cells, the truncated protein incorporates into cardiac sarcomeres, leading to aberrant Z-disc structure. In homozygous stop-gain cells, affinity-purification mass spectrometry reveals an intricate ACTN2 interactome with sarcomere and sarcolemma-associated proteins. Loss of the C-terminus of ACTN2 disrupts interaction with ACTN1 and GJA1, two sarcolemma-associated proteins, that may lead to the clinical arrhythmic and relaxation defects. The causality of the stop-gain mutation was verified using CRISPR-Cas9 gene editing. Together, these data advance our understanding of the role of ACTN2 in the human heart and establish recessive inheritance of ACTN2 truncation as causative of disease.

genetics↗

bioRxiv2019

Differential response trajectories to acute exercise in blood and muscle

A physically active lifestyle is essential for maintaining health, and is a powerful way to prevent chronic disease. However, the molecular mechanisms that drive exercise adaptation and transduce its beneficial effects, are incompletely understood. Here, we combined data from 49 studies that measured the whole transcriptome in humans before and after exercise to provide the power to draw novel observations not seen in any individual study alone. The resulting curated and standardized resource includes samples from skeletal muscle (n=1,260) and blood (n=726) in response to endurance or resistance exercise and training. Using a linear mixed effects meta-regression model selection strategy, we detected specific time patterns and novel regulatory modulators of the acute exercise response. Acute and long term responses to exercise were transcriptionally distinct. Exercise induced a more pronounced inflammatory response in skeletal muscle of older individuals. We identified multiple sex-specific response genes, where MTMR3 is a novel exercise-regulated gene. These results deepen our understanding of the transcriptional responses to exercise and provide a powerful resource for future research efforts in exercise physiology and medicine.

physiology↗

bioRxiv2019

An epigenetic clock for skeletal muscle

BackgroundAgeing is associated with DNA methylation changes in all human tissues, and epigenetic markers can estimate chronological age based on DNA methylation patterns across tissues. However, the construction of the original pan-tissue epigenetic clock did not include skeletal muscle samples, and hence exhibited a strong deviation between DNA methylation and chronological age in this tissue. MethodsTo address this, we developed a more accurate, muscle-specific epigenetic clock based on the genome-wide DNA methylation data of 682 skeletal muscle samples from 12 independent datasets (18-89 years old, 22% women, 99% Caucasian), all generated with Illumina HumanMethylation arrays (HM27, HM450 or HMEPIC). We also took advantage of the large number of samples to conduct an epigenome-wide association study (EWAS) of age-associated DNA methylation patterns in skeletal muscle. ResultsThe newly developed clock uses 200 CpGs to estimate chronological age in skeletal muscle, 16 of which are in common with the 353 CpGs of the pan-tissue clock. The muscle clock outperformed the pan-tissue clock, with a median error of only 4.6 years across datasets (vs 13.1 years for the pan-tissue clock, p < 0.0001) and an average correlation of {rho} = 0.62 between actual and predicted age across datasets (vs {rho} = 0.51 for the pan-tissue clock). Lastly, we identified 180 differentially methylated regions (DMRs) with age in skeletal muscle at a False Discovery Rate < 0.005. However, Gene Set Enrichment Analysis did not reveal any enrichment for Gene Ontologies. ConclusionsWe have developed a muscle-specific epigenetic clock that predicts age with better accuracy than the pan-tissue clock. We implemented the muscle clock in an R package called MEAT available on Bioconductor to estimate epigenetic age in skeletal muscle samples. This clock may prove valuable in assessing the impact of environmental factors, such as exercise and diet, on muscle-specific biological ageing processes.

bioinformatics↗