Biology subjects

Schenk, S.

Publications and source records attributed to Schenk, S..

18 recordsLinked to original sources

bioRxiv2026

Cardiomyocyte Perm1 sustains cardiac bioenergetic reserve and exercise capacity

Objective: Mitochondrial oxidative capacity in striated muscle is governed by the PGC-1/ERR transcriptional axis, which controls not only steady-state respiration but the capacity to expand energy production when demand rises. Whether this reserve function requires dedicated downstream effectors, and whether its loss is detectable at rest, remains unclear. We asked whether Perm1, a striated muscle-specific PGC-1/ERR-induced regulator, is required cell-autonomously for cardiac bioenergetic reserve. Methods: We generated cardiomyocyte-specific Perm1 knockout mice using alphaMHC-nCre, complemented by an adult tamoxifen-inducible alphaMHC-MerCreMer model, and assessed cardiac development, structure, and function longitudinally through 12 months of age in both sexes. We evaluated mitochondrial function by high-resolution respirometry, transmission electron microscopy, and molecular profiling. We tested energetic capacity under load by treadmill exercise with tissue ATP quantification and by beta-adrenergic stimulation of cultured neonatal cardiomyocytes. Results: Perm1 deletion did not perturb embryonic cardiac development, and neither constitutive nor adult-onset deletion impaired cardiac structure, systolic function, or diastolic function through 12 months. Despite this preserved resting phenotype, mitochondrial respiration was reduced by 20 - 25% across complex I- and complex I+II-supported conditions, without changes in citrate synthase activity, mtDNA copy number, or OXPHOS subunit abundance. Instead, the MICOS components IMMT (MIC60) and CHCHD3 (MIC19) were selectively reduced, and mitochondrial subpopulations shifted toward fewer subsarcolemmal and more interfibrillar mitochondria, with unchanged total mitochondrial density. Functionally, Perm1-deficient mice of both sexes showed reduced treadmill capacity at 6 and 12 months and failed to maintain cardiac ATP during exercise at a submaximal workload, while skeletal muscle ATP and plasma lactate were unaffected. This deficit was cardiomyocyte-autonomous: beta-adrenergic stimulation increased ATP content in control cardiomyocytes, but Perm1 knockdown reduced this response. Conclusions. Perm1 is a cardiomyocyte-intrinsic determinant of bioenergetic reserve, dispensable for resting cardiac function but required to expand ATP production under increased demand. These findings identify a mode of metabolic regulation that is invisible to resting functional phenotyping.

physiology↗

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

Systems modeling of mitochondrial dynamics in different exercise regimes

Exercise stimulates skeletal muscle signaling and mitochondrial metabolism. Emerging evidence shows that mitochondrial dynamics (i.e., fission and fusion) could be regulated by exercise. Yet, there are knowledge gaps on the following questions: (i) which upstream signals are necessary and sufficient to bias mitochondria toward fission versus fusion? (ii) How does cellular energy status and ROS partition control between DRP1 and MFN/OPA1? And (iii) which combinations of intensity and duration produce similar cytosolic signals but distinct mitochondrial remodeling? To address these gaps, we developed an integrative computational framework that connects exercise regimens to mitochondria fission-fusion machinery by linking blood-myofiber energetics in cytosol and mitochondria to skeletal muscle signaling network. The influence of three exercise regimen (i.e., sprint, resistance, and endurance) on mitochondrial fission and fusion was simulated. Classified qualitative validation of signaling network model against studies not used in developing the model achieved 80% accuracy. The model predicts regimen-specific dynamics starting with acute DRP1-driven fission during exercise followed by MFN1/2-OPA1-mediated re-fusion as energy stress declines, consistent with a cyclical triage-then-rebuild paradigm. Changes are most pronounced and sustained with endurance, sharp but brief with sprint, and minimal with resistance. Global sensitivity analysis identified AMPK/PGC-1[->]MFN1/2 as dominant fusion drivers, ROS and AMPK[->]MFF/DRP1 as primary fission switches, and Ca{superscript 2}-calmodulin, ERK, and LKB1/AMPK as shared regulators of fission and fusion. Our model also predicts that an endurance base, augmented with 1-2 weekly high intensity interval traning (HIIT)/ sprint interval training (SIT) sessions could maximize AMPK-ROS pulses and mitochondrial fission-fusion. This framework unifies muscles signaling logic with the energetic state to explain how intensity-volume combinations, bout spacing, and kinase modulation tune mitochondrial remodeling, yielding testable predictions for optimizing training and adjuvant therapies for enhanced human performance.

systems biology↗

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↗

bioRxiv2025

An experimental test of the influence of microbial manipulation on sugar kelp (Saccharina latissima) supports the the core influences host function hypothesis

Kelp are valued for a wide range of commercial products and for their role in kelp forest ecosystems, making kelp cultivation a rapidly expanding economic sector. Microbes associated with kelp and other macroalgae play a critical role in processes such as nutrient exchange, chemical signaling, and defense against pathogens. Thus, manipulating the microbiome to enhance macroalgal growth and resilience is a promising yet underexplored approach for sustainable kelp cultivation. The core microbiome hypothesis suggests that the bacteria that are consistently found on a host (the core microbes) are likely to have a disproportionate impact on host biology, making them an attractive target for microbiome manipulation. In this study, we surveyed wild Saccharina latissima and their surrounding environment to identify core bacterial taxa, compared them to cultivated kelp, and experimentally tested how cultured bacterial isolates affect kelp development. We found that core bacteria are nearly absent in cultivated juvenile sporophytes in nurseries but eventually colonized them after outplanting to ocean farm sites. Bacterial inoculants had both positive and negative effects on kelp development. Notably, the strength of association of a bacterial genus with kelp in the wild positively correlated with its impact on gametophyte settlement and sporophyte development in kelp co-culture experiments, aligning with predictions from the core microbiome influences host function hypothesis. These findings affirm the feasibility of using microbial manipulations to improve current kelp aquaculture practices and provide a framework for developing these techniques. IMPORTANCEMicroorganisms consistently associated with hosts are widely thought to be more likely to impact host biology and health. However, this intuitive concept has not been experimentally evaluated. This study formalizes this concept as the Core microbiome Influences Host Function hypothesis and experimentally tests this hypothesis in sugar kelp (Saccharina). The distribution of bacteria on wild kelp and core microbes were first identified by compiling a broad dataset of the kelp microbiome sampled across space and time. Bacterial cultures were isolated from the surface of sugar kelp and individually grown in laboratory co-culture with sugar kelp spores to assess the ability of bacterial isolates to influence kelp growth and development. In support of the core influences host function hypothesis, isolates belonging to bacterial genera that are more strongly associated with wild sugar kelp are more likely to influence development in laboratory experiments.

ecology↗

bioRxiv2025

Themis and Grb2 form a constitutive structural hub in T cell receptor signalling

Positive selection of thymocytes is essential for laying the foundations of the mammalian immune system that include the T cell repertoire, self-tolerance, and prevention of autoimmunity. Themis, the archetypal member of a metazoan protein family featuring distinctive CABIT domains, crucially regulates thymocyte positive selection by linking signalling by the T cell receptor (TCR) to the linker of activation of TCR (LAT). Intriguingly, Themis has been proposed to function via a constitutive complex with the multifunctional adaptor Grb2. Although poised to represent a paradigm shift in our understanding of TCR signalling, the structural and mechanistic basis of such an assembly has remained enigmatic. Here, we present the cryo-EM structure of Themis in complex with Grb2, which reveals how the tandem CABIT domains of Themis engulf the C-terminal SH3 domain of Grb2 (Grb2SH3C) to enable its latching onto the proline rich sequence of Themis. The remaining two domains of Grb2 adopt at least three conformational poses set to interact with other binding partners such as Sos1. Structural insights from unbound Themis unmask the pronounced flexibility of the CABIT domains of Themis, which becomes ordered upon binding to Grb2 to create a binding hotspot for their constitutive complex. Indeed, Themis variants that abrogate interactions with Grb2 also fail to activate the tyrosine phosphatase SHP-1 after TCR stimulation, analogous to the functional phenotype of Themis-deficient cells. Collectively, our study draws the blueprint of the Themis-Grb2 complex as a dynamic structural hub in T cell development.

immunology↗

bioRxiv2025

Novel pink-spot disease in North American kelpnurseries

Macroalgal cultivation is a growing industry in North America, but is well established in Asia and Africa, where macroalgal disease cause crop losses, placing a significant economic burden on farmers. As kelp cultivation intensifies in North America, kelp disease prevalence is expected to increase in tandem. With input from the kelp-growing community through an online survey, we describe the prevalence of a novel kelp disease, pink-spot disease, which has been observed in Canada and the United States on Saccharina latissima, Alaria marginata, Nereocystis luetkeana, and Macrocystis tenuifolia. Eight of the fourteen (57%) surveyed kelp growers report bright pink spots (pink-spot disease) on their kelp spools in the land-based nursery stage. Along with the grower survey, we conducted 16S rRNA amplicon sequencing in 2021 and 2022 to investigate the causative agent of pink-spot disease and associated bacterial community changes on infected Saccharina latissima (sugar kelp) spools. Our data in both years show that a member of the genus Algicola is enriched on visibly diseased spool regions compared to asymptomatic spool regions and may be the causative agent of pink-spot disease. As macroalgal cultivation continues to intensify, monitoring diseases is important to mitigate potential negative impacts.

ecology↗

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

Monthly macroalgal surveys reveal a diverse and dynamic community in an urban intertidal zone

Baseline data are critical to measuring how communities shift in response to climate change and anthropogenic activity. Macroalgae are marine foundation species that are vulnerable to climate change, but baseline macroalgal biodiversity data are lacking for many areas of British Columbia, particularly at a high temporal resolution over years. This presents an obstacle for measuring how communities change in response to shifting average conditions as well as after extreme events, such as the 2021 heat dome. To increase baseline macroalgae biodiversity data in British Columbia, we established a monthly transect-based macroalgal survey in 2021 at an urban intertidal site with a low-cost and easily replicable survey protocol, in addition to publishing a previously unpublished 1983-1984 historical dataset of the same area. Our datasets and our survey protocol are freely available. Over 35 months we have recorded 61 taxa of macroalgae, including the canopy forming kelp Nereocystis luetkeana and the introduced fucoid Sargassum muticum. Surveying throughout the year at regular intervals has revealed large-scale seasonal shifts in macroalgal community composition, the timing of kelp recruitment, and a decrease in abundance of Fucus distichus in the upper intertidal zone over multiple years. Our publicly accessible data constitute the most comprehensive survey of intertidal macroalgal diversity in Burrard Inlet, illustrating how simple surveying methods can provide high resolution records of macroalgae biodiversity, particularly in easily accessible urban environments.

ecology↗

bioRxiv2024

Intrinsic skeletal muscle function and contraction-stimulated glucose uptake do not vary by time-of-day in mice

A growing body of data suggests that skeletal muscle contractile function and glucose metabolism vary by time-of-day, with chronobiological effects on intrinsic skeletal muscle properties being proposed as the underlying mediator. However, no studies have directly investigated intrinsic contractile function or glucose metabolism in skeletal muscle over a 24 h circadian cycle. To address this, we assessed intrinsic contractile function and endurance, as well as contraction-stimulated glucose uptake, in isolated extensor digitorum longus and soleus from female mice at four times-of-day (Zeitgeber Times 1, 7, 13, 19). Significantly, while both muscles demonstrated circadian-related changes in gene expression, intrinsic contractile function, endurance, and contraction-stimulated glucose uptake were not different between the four time points. Overall, these results demonstrate that time-of-day variation in exercise performance and the glycemia-reducing benefits of exercise are not due to chronobiological effects on intrinsic muscle function or contraction-stimulated glucose uptake. Impact statementEx vivo testing demonstrates that there is no time-of-day variation in the intrinsic contractile properties of skeletal muscle (including no effect on force production or endurance) or contraction-stimulated glucose uptake.

physiology↗

bioRxiv2024

Insights into post-translational regulation of skeletal muscle contractile function by the acetyltransferases, p300 and CBP

Mice with skeletal muscle-specific inducible double knockout of the lysine acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP-response element-binding protein binding protein), referred to as i-mPCKO, demonstrate a dramatic loss of contractile function in skeletal muscle and ultimately die within 7 days. Given that many proteins involved in ATP generation and cross-bridge cycling are acetylated, we investigated whether these processes are dysregulated in skeletal muscle from i-mPCKO mice and thus could underlie the rapid loss of muscle contractile function. Just 4-5 days after inducing knockout of p300 and CBP in skeletal muscle from adult i-mPCKO mice, there was [~]90% reduction in ex vivo contractile function in the extensor digitorum longus (EDL) and a [~]65% reduction in in vivo ankle dorsiflexion torque, as compared to wildtype (WT; i.e. Cre negative) littermates. Despite the profound loss of contractile force in i-mPCKO mice, there were no genotype-driven differences in fatigability during repeated contractions, nor were there genotype differences in mitochondrial specific pathway enrichment of the proteome, intermyofibrillar mitochondrial volume or mitochondrial respiratory function. As it relates to cross-bridge cycling, remarkably, the overt loss of contractile function in i-mPCKO muscle was reversed in permeabilized fibers supplied with exogenous Ca2+ and ATP, with active tension being similar between i-mPCKO and WT mice, regardless of Ca2+ concentration. Actin-myosin motility was also similar in skeletal muscle from i-mPCKO and WT mice. In conclusion, neither mitochondrial abundance/function, nor actomyosin cross-bridge cycling, are the underlying driver of contractile dysfunction in i-mPCKO mice. New & NoteworthyThe mechanism underlying dramatic loss of muscle contractile function with inducible deletion of both p300 and CBP in skeletal muscle remains unknown. Here we find that impairments in mitochondrial function or cross-bridge cycling are not the underlying mechanism of action. Future work will investigate other aspects of excitation-contraction coupling, such as Ca2+ handling and membrane excitability, as contractile function could be rescued by permeabilizing skeletal muscle, which provides exogenous Ca2+ and bypasses membrane depolarization.

cell biology↗

bioRxiv2023

Exploring the impact of microbial manipulation on the early development of kelp (Saccharina latissima) using an ecological core microbiome framework.

Kelp cultivation is a rapidly expanding economic sector, as kelp are valued for a wide range of commercial products and for restoration of kelp forest ecosystems. Microbes associated with kelp and other macroalgae play a critical role in processes such as nutrient exchange, chemical signaling, and defense against pathogens. Thus, manipulating the microbiome to enhance macroalgal growth and resilience is a promising, but largely untested, tool in sustainable kelp cultivation. The core microbiome hypothesis suggests that bacteria that are consistently found on a host (the core microbes) are likely to have a disproportionate impact on host biology, making them an attractive target for microbiome manipulation. Here, we surveyed wild Saccharina latissima and their surrounding environment to identify core bacterial taxa, compared to cultivated kelp, and experimentally tested the effect of cultured bacterial isolates on kelp development. We find that core bacteria are nearly absent in cultivated juvenile sporophytes in nurseries but eventually colonized after outplanting kelp to ocean farm sites. We find that bacterial inoculants can have both positive and negative effects on kelp development. In line with predictions from the core microbiome hypothesis, we find a positive correlation between the frequency of the bacterial genus in the wild and the bacterial effect on the number of sporophytes in kelp co-culture experiments. IMPORTANCEThe core microbiome hypothesis suggests that symbiotic microorganisms consistently associated with hosts have functional effects on host biology and health. However, there is a lack of evidence to either support or refute this idea. This study surveys the distribution of bacteria on wild and cultivated kelp to identify the core microbiome and tests the ability of bacterial isolates cultured from the surface of wild kelp to influence kelp growth and development in laboratory microbial manipulation experiments. The frequency of bacterial genera on wild kelp was positively correlated with influence on kelp development in laboratory experiments, providing support for the core microbiome hypothesis.

ecology↗

bioRxiv2023

Low salinity significantly alters the bacterial community of the marine foundation species Saccharina latissima (sugar kelp)

As climate change progresses, the intensity and variability of freshwater outflow into the ocean are predicted to increase. The resulting increase in low-salinity events will be a source of stress for Saccharina latissima and potentially Saccharina-associated bacteria. Bacteria influence host health and can facilitate or hinder host survival and acclimation to stressful abiotic conditions. Therefore, understanding how bacterial communities change under abiotic stress is critical to understand how abiotic stress will affect kelp physiology. We investigated the effect of low-salinity stress on Saccharina-associated bacteria and the host by surveying the bacterial community associated with Saccharina and the surrounding environment across naturally occurring salinity gradients during the spring freshet across two years at four field sites with contrasting salinity profiles around Vancouver, Canada (519 samples), coupled with salinity manipulation experiments repeated eight times (269 samples). Overall, Saccharina harbours a stable core bacterial community, which decreases in relative abundance under abiotic stress. In the field, both salinity and temperature shape the bacterial community, with temperature having higher explanatory power most of the time. In the lab, we confirm that the patterns observed in the field can be replicated by manipulating salinity alone. Decreased relative abundance of core bacteria and increased community dissimilarity in low salinity, in both the lab and field, suggest that host filtering is significantly impaired in low salinity. In the context of a stable host-associated core bacterial community during non-stressful conditions, the change in the community composition observed during conditions of abiotic stress indicates a host stress response.

ecology↗

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↗

bioRxiv2022

Increasing Muscle Hypertrophy with a Natural Product Designed to Inhibit SIRT1

Muscle mass and strength are predictors of longevity. We have previously identified a series of molecular brakes that slow muscle growth in response to stress. One potential stress that we hypothesized would limit muscle growth is caloric stress through the activation of SIRT1. We therefore identified natural product inhibitors of SIRT1 and tested their effects on load-induced increases in muscle fiber cross-sectional area (fCSA) using an incomplete factorial design. Supplying varying amounts of three natural products for the full two-week period of overload resulted in increases in fCSA that varied from -2 to 113%. Using these data, we produced a model that predicted the optimal combination and concentration of each natural product and validated this model in a separate cohort of animals. Following two weeks of overload, fCSA in the optimal group increased 62%, whereas in the placebo fCSA increased only 3%. The greater increase in fCSA was not the result of an increase in ribosomal mass. In fact, the optimal group showed significantly less of the 5 external transcribed spacer, a marker of 47S ribosomal RNA synthesis, and a trend for decreased total RNA. In spite of the lower ribosome mass, the increase in protein synthesis was similar, suggesting that the natural product cocktail may be increasing ribosomal efficiency rather than capacity. These data suggest that inhibition of SIRT1, together with exercise, may be useful in increasing muscle fCSA.

physiology↗

bioRxiv2019

Maternal Obesity and Western-style Diet Impair Fetal and Juvenile Offspring Skeletal Muscle Insulin-Stimulated Glucose Transport in Nonhuman Primates

Infants born to mothers with obesity have a greater risk for childhood obesity and metabolic diseases; however, the underlying biological mechanisms remain poorly understood. We used a nonhuman primate model to investigate whether maternal obesity combined with a western-style diet (WSD) impairs offspring muscle insulin action. Briefly, adult females were fed a control (CON) or WSD prior to and during pregnancy and lactation. Offspring were weaned to a CON or WSD. Muscle glucose uptake and insulin signaling were measured ex vivo in fetal and juvenile offspring. In vivo signaling was evaluated before and after an intravenous insulin bolus just prior to weaning. We find that fetal muscle exposed to maternal WSD had reduced insulin-stimulated glucose uptake and impaired insulin signaling. In juvenile offspring, insulin-stimulated glucose uptake was similarly reduced by both maternal and post-weaning WSD. Analysis of insulin signaling activation revealed distinct changes between fetal and post-weaning WSD exposure. We conclude that maternal WSD leads to a persistent decrease in insulin-stimulated glucose uptake in juvenile offspring even in the absence of increased offspring adiposity or markers of systemic insulin resistance. Switching offspring to a healthy diet did not ameliorate the effects of maternal WSD suggesting earlier interventions may be necessary.

physiology↗