Biology subjects

Hevener, A. L.

Publications and source records attributed to Hevener, A. L..

9 recordsLinked to original sources

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

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

Exercise training remodels inter-organ endocrine networks

Exercise induces organism-wide molecular adaptations, partly mediated by humoral factors released in response to acute and chronic physical activity. However, the extent and specificity of endocrine effects from training-induced secreted factors remain unclear. Here, we applied systems genetics approaches to quantify inter-organ endocrine networks using multi-tissue transcriptomics and proteomics data collected from endurance-trained rats in The Molecular Transducers of Physical Activity Consortium (MoTrPAC). Eight weeks of endurance training significantly altered both the magnitude and specificity of endocrine effects across multiple origin-target tissue pairs. Subcutaneous white adipose tissue emerged as a key endocrine regulator impacted by training, while extracellular matrix-derived factors were identified as globally regulated secretory features in trained vs sedentary animals. Notably, secretory Wnt signaling factors were identified as key mediators of exercise-induced endocrine adaptations in multiple tissues. Our systems genetics framework provides an unprecedented atlas of inter-organ communication significantly remodeled by endurance exercise, serving as a valuable resource for novel exerkine discovery.

physiology↗

bioRxiv2025

Markers of mitochondrial function and oxidative metabolism in female skeletal muscle do not display intrinsic circadian regulation

Mitochondria are key regulators of metabolism and ATP supply in skeletal muscle, while circadian rhythms influence many physiological processes. However, whether mitochondrial function is intrinsically regulated in a circadian manner in mouse skeletal muscle is inadequately understood. Accordingly, we measured post-absorptive transcript abundance of markers of mitochondrial biogenesis, dynamics, and metabolism (extensor digitorum longus [EDL], soleus, gastrocnemius), protein abundance of electron transport chain complexes (EDL and soleus), enzymatic activity of SDH (tibialis anterior and plantaris), and maximum uncoupled respiration (tibialis anterior) in different skeletal muscles from female C57BL/6NJ mice at four zeitgeber times (ZT), ZT 1, 7, 13, and 19. Our findings demonstrate that markers of mitochondrial function and oxidative metabolism do not display intrinsic time-of-day regulation at the gene, protein, enzymatic, or functional level. The core-clock genes Bmal1 and Dbp exhibited intrinsic circadian rhythmicity in skeletal muscle (i.e., EDL, soleus, gastrocnemius) and circadian amplitude varied by muscle type. These findings demonstrate that female mouse skeletal muscle does not display circadian regulation of markers of mitochondrial function or oxidative metabolism over 24 hours.

physiology↗

bioRxiv2024

A genome-wide ATLAS of liver chromatin architecture reveals that sex dictates diet-induced nucleosome dynamics

The three-dimensional organization of the genome plays an important role in cellular function. Alterations between open and closed chromatin states contributes to DNA binding, collaborative transcriptional activities and informs post-transcriptional processing. The liver orchestrates systemic metabolic control and has the ability to mount a rapid adaptive response to environmental challenges. We interrogated the chromatin architecture in liver under different dietary cues. Using ATAC-seq, we mapped over 120,000 nucleosome peaks, revealing a remarkably preserved hepatic chromatin landscape across feeding conditions. Stringent analysis of nucleosome rearrangements in response to diet revealed that sex is the dominant factor segregating changes in chromatin accessibility. A lipid-rich diet led to a more accessible chromatin confirmation at promoter regions in female mice along with enrichment of promoter binding CCAAT-binding domain proteins. Male liver exhibited stronger binding for nutrient sensing nuclear receptors. Integrative analysis with gene expression corroborated a role for chromatin states in informing functional differences in metabolic traits. We distinguished the impact of gonadal sex and chromosomal sex as determinants of chromatin modulation by diet using the Four Core Genotypes mouse model. Our data provide mechanistic evidence underlying the regulation for the critical sex-dimorphic GWAS gene, Pnpla3. In summary, we provide a comprehensive epigenetic resource in murine liver that uncovers the complexity of chromatin dynamics in response to diet and sex. HighlightsATAC-Seq, RNA-Seq, and FCG model-integrated analysis unravel sex differences in chromatin accessibility and transcriptome responses to dietary challenges. Lipid-rich diet led to sex-biased chromatin confirmation at promoter regions. Gonadal sex emerged as the most prevalent determinant of the sex bias hepatic chromatin modulation by lipid-rich diets. The critical sex-dimorphic GWAS gene Pnpla3 is suppressed by testosterone, which underlies hepatic differences in expression between the sexes.

molecular biology↗

bioRxiv2023

Leveraging genetic correlation structure to target discrete signaling mechanisms across metabolic tissues

Abstract/IntroductionInter-organ communication is a vital process to maintain physiologic homeostasis, and its dysregulation contributes to many human diseases. Beginning with the discovery of insulin over a century ago, characterization of molecules responsible for signal between tissues has required careful and elegant experimentation where these observations have been integral to deciphering physiology and disease. Given that circulating bioactive factors are stable in serum, occur naturally, and are easily assayed from blood, they present obvious focal molecules for therapeutic intervention and biomarker development. For example, physiologic dissection of the actions of soluble proteins such as proprotein convertase subtilisin/kexin type 9 (PCSK9) and glucagon-like peptide 1 (GLP1) have yielded among the most promising therapeutics to treat cardiovascular disease and obesity, respectively1-4. A major obstacle in the characterization of such soluble factors is that defining their tissues and pathways of action requires extensive experimental testing in cells and animal models. Recently, studies have shown that secreted proteins mediating inter-tissue signaling could be identified by "brute-force" surveys of all genes within RNA-sequencing measures across tissues within a population5-9. Expanding on this intuition, we reasoned that parallel strategies could be used to understand how individual genes mediate signaling across metabolic tissues through correlative analyses of gene variation between individuals. Thus, comparison of quantitative levels of gene expression relationships between organs in a population could aid in understanding cross-organ signaling. Here, we surveyed gene-gene correlation structure across 18 metabolic tissues in 310 human individuals and 7 tissues in 103 diverse strains of mice fed a normal chow or HFHS diet. Variation of genes such as FGF21, ADIPOQ, GCG and IL6 showed enrichments which recapitulate experimental observations. Further, similar analyses were applied to explore both within-tissue signaling mechanisms (liver PCSK9) as well as genes encoding enzymes producing metabolites (adipose PNPLA2), where inter-individual correlation structure aligned with known roles for these critical metabolic pathways. Examination of sex hormone receptor correlations in mice highlighted the difference of tissue-specific variation in relationships with metabolic traits. We refer to this resource as Gene-Derived Correlations Across Tissues (GD-CAT) where all tools and data are built into a web portal enabling users to perform these analyses without a single line of code (gdcat.org). This resource enables querying of any gene in any tissue to find correlated patterns of genes, cell types, pathways and network architectures across metabolic organs.

physiology↗

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↗

bioRxiv2022

Genetic variation of human myokine signaling is dominated by biologic sex and sex hormones

Abstract/IntroductionProteins secreted from skeletal muscle, termed myokines, allow muscle to impact systemic physiology and disease. Myokines play critical roles in a variety of processes, including metabolic homeostasis, exercise improvements, inflammation, cancer and cognitive functions1-6. Despite the clear relevance of these factors in mediating a multitude of physiological outcomes, the genetic architecture, regulation and functions of myokines, as well as degree of conservation of these communication circuits remains inadequately understood. Given that biologic sex controls critical aspects of nearly every physiologic outcome, it is essential to consider when relating specific mechanisms to complex genetic and metabolic interactions. Specifically, many metabolic traits impacted by myokines show striking sex differences arising from hormonal7-10, genetic7,11 or gene-by-sex interactions12,13. In this study, we performed a genetic survey of myokine gene regulation and cross-tissue signaling in humans where sex as a biological variable was emphasized. While expression levels of a majority of myokines and cell proportions within skeletal muscle showed little differences between males and females, nearly all significant cross-tissue enrichments operated in a sex-specific or hormone-dependent fashion; in particular, with estrogens. These sex- and hormone-specific effects were consistent across key metabolic tissues: liver, pancreas, hypothalamus, intestine, heart, visceral and subcutaneous adipose tissue. Skeletal muscle estrogen receptor enrichments across metabolic tissues appeared stronger than androgen receptor and, surprisingly, ~3-fold higher in males compared to females. To define the causal roles of estrogen signaling on myokine gene expression and functions, we generated male and female mice which lack estrogen receptor (Esr1) specifically in skeletal muscle and integrated global RNA-Sequencing with human data. These analyses highlighted mechanisms of sex-dependent myokine signaling conserved between species, such as myostatin enriched for divergent substrate utilization pathways between sexes. Several other sex-dependent mechanisms of myokine signaling were uncovered, such as muscle-derived TNF exerting stronger inflammatory signaling in females compared to males and GPX3 as a male-specific link between glycolytic fiber abundance and hepatic inflammation. Collectively, we provide the first genetic survey of human myokines and highlight sex and estrogen receptor signaling as critical variables when assaying myokine functions and how changes in cell composition impact other metabolic organs.

physiology↗

bioRxiv2019

A Pro-Diabetogenic mtDNA Polymorphism in the Mitochondrial-Derived Peptide, MOTS-c

Type 2 Diabetes (T2D) is an emerging public health problem in Asia. An Asian mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n=27,527, J-MICC, MEC, and TMM) showed that males but not females with the C-allele exhibit a higher prevalence of T2D. Furthermore, in J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro. Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.

genetics↗