Energetic Demands Research Articles

Sleeping while diving: seals at sea drift in and out of sleep at depth

In mammals, sleep is critical and ubiquitous. However, in marine mammals that spend months or entire lifetimes at sea, sleep can limit access to air and foraging opportunities and leave animals vulnerable to predation. Large, deep-diving northern elephant seals (Mirounga angustirostris) travel thousands of kilometers and spend up to 7 months at sea in search of food. We posited that combined demands to feed and avoid predators would strongly restrict aquatic sleep in seals. We built a portable, non-invasive system to simultaneously monitor electroencephalogram (EEG), electrocardiogram (ECG), three-dimensional motion, and swimming behavior. EEG activity of 13 young (< 3-years-old) female northern elephant seals (N = 5 in the lab, N = 8 in the wild [N = 3 at sea]) revealed that total sleep time was indeed strongly restricted at sea compared to on land (> 6-fold difference; 10.8 ± 3.0 h/day on land, 1.7 ± 0.7 h/day at sea). Seals at sea slept during short naps (< 20 min) while resting on the ocean floor (64-249 m deep) or drifting through the water column (82-377 m deep). REM sleep in mammals co-occurs with sleep paralysis. Our data support the presence of sleep paralysis through a persistent supine inversion (belly-up posture) whenever the seal was in REM (100% of REM sleep in the open ocean). Unexpectedly, elephant seals at sea exhibited a large proportion of REM sleep (29.1 ± 4.3% of at-sea total sleep time), compared to aquatic sleep in captive Caspian seals, harp seals, walruses, and fur seals (11%, 6%, 5%, and 1% respectively). This suggests that sleep at depth allows seals to drift safely in and out of sleep paralysis. However, time for sleep is limited by near-constant foraging to support high energetic demands due to their large body size. The extreme flexibility in sleep duration exhibited by northern elephant seals is unprecedented among mammals – approaching that which is observed in migrating birds. These insights into sleep for a large, highly mobile marine mammal can contribute to our understanding of sleep’s function and pathology across mammals, including humans. Funding: NSF Graduate Resesarch Fellowship, Laurel Clark Sea to Space Physiology Research Grant, ARCS Fellowship, Sooy Graduate Fellowship, National Geographic Early Career Grant, Special Research Grant – UC Santa Cruz, Joint Industry Project (JIP2207-23) [DPC], Office of Naval Research (Grants # N00014-08-1-1195 [DPC], N00014-18-1-2822 [DPC], N00014-00-1-0880 [DPC], N00014-03-1-0651 [DPC], N00014-08-1-1195 [DPC], N00014-20-1-2762 [TMW], N00014-19-1-2178 [TMW]) 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.

30 Intrinsic skeletal muscle mitochondrial function decreases while mitochondrial volume density increases from 6 months to 3-years-old in Thoroughbreds

As the primary source of cellular energy, mitochondria are critical for athletic performance, and the intricacies of mitochondrial electron transfer may be related to Thoroughbred race performance. However, little is known about specific mitochondrial adaptations to growth in the equine athlete. To test the hypothesis that mitochondrial metrics would increase with age, gluteus medius samples were collected from the same Thoroughbred horses as weanlings (4 colts, 9 fillies; mean ± SD, 6 ± 1mo), yearlings (4 colts, 10 fillies; 20 ± 1mo), 2-year-olds (2yo; 3 geldings, 10 mares; 32 ± 1mo), and 3yo (2 geldings, 3 mares; 44 ± 1mo) from the same Kentucky farm over 4 years. Thoroughbreds were broke to ride in August of their yearling year then began race training. Mitochondrial oxidative phosphorylation (P) and electron transfer (E) capacities were determined via high-resolution respirometry. Citrate synthase (CS) and cytochrome c oxidase (CCO) activities were quantified as measures of mitochondrial volume density and function, respectively. Data were analyzed using PROC MIXED in SASv9.4 with age and sex as fixed effects, sire and dam as random effects, and age as a repeated effect with horse as the subject. Intrinsic (relative to CS activity) CCO activity, P supported by complex I (PCI), maximal P (PCI+II), and maximal E (ECI+II) weregreatest in weanlings compared with all other ages (P ≤ 0.003) and greater in yearlings than 2yo (P ≤ 0.05). Intrinsic E supported by complex II only (ECII) was greater in weanlings than 2 or 3yo (P ≤ 0.01) and greater in yearlings than 2yo (P ≤ 0.04). Weanlings also had a greater contribution of PCI+II to ECI+II than yearlings, 2yo, or 3yo (P ≤ 0.05). However, CS activity was greatest in 3yo (P ≤ 0.03) and lowest in weanlings (P ≤ 0.0001) with yearlings and 2yo intermediate, indicating expansion of the mitochondrial network with age and training. Additionally, 3yo had the greatest integrative (per mg tissue) PCI of all ages (P ≤ 0.005). Two and 3yo had greater integrative PCI+II, ECI+II, and ECII capacities than weanlings (P ≤ 0.05). Overall, weanlings had the greatest intrinsic mitochondrial capacities and function but 2 and 3yo Thoroughbreds had greater mitochondrial volume density resulting in greater integrative capacities. Skeletal muscle mitochondria of young Thoroughbreds appear to adapt to meet energetic demands of growth and race training by increasing volume density rather than intrinsic capacity, but further research is warranted to characterize the impacts of various training programs on mitochondrial metrics.

Disproportionate Expression of ATM in Cerebellar Cortex During Human Neurodevelopment

Cerebellar neurodegenerationis a classical feature of ataxia telangiectasia (A-T), an autosomal recessive condition caused by loss-of-function mutation of the ATM gene, a gene with multiple regulatory functions. The increased vulnerability of cerebellar neurones to degeneration compared to cerebral neuronal populations in individuals with ataxia telangiectasia implies a specific importance of intact ATM function in the cerebellum. We hypothesised that there would be elevated transcription of ATM in the cerebellar cortex relative to ATM expression in other grey matter regions during neurodevelopment in individuals without A-T. Using ATM transcription data from the BrainSpan Atlas of the Developing Human Brain, we demonstrate a rapid increase in cerebellar ATM expression relative to expression in other brain regions during gestation and remaining elevated during early childhood, a period corresponding to the emergence of cerebellar neurodegeneration in ataxia telangiectasia patients. We then used gene ontology analysis to identify the biological processes represented in the genes correlated with cerebellar ATM expression. This analysis demonstrated that multiple processes are associated with expression of ATM in the cerebellum, including cellular respiration, mitochondrial function, histone methylation, and cell-cycle regulation, alongside its canonical role in DNA double-strand break repair. Thus, the enhanced expression of ATM in the cerebellum during early development may be related to the specific energetic demands of the cerebellum and its role as a regulator of these processes.

Parasitic fauna of farmed freshwater ornamental sutchi catfish (Pangasiandon hypophthalmus) and silver dollar (Metynnis hypsauchen) in Alborz province, Iran.

Parasitic infestations are one of the most significant problems in global aquaculture. In addition to direct economic losses due to significant mortalities, parasites may have a significant negative impact on the fish's behaviour, energetic demands, trophic position, interspecific competition, growth rate, and reproductive function. We conducted the present study to evaluate the infection status of parasitic pathogens in freshwater sutchi catfish (Pangasianodon hypophthalmus) and silver dollar (Metynnis hypsauchen) farmed in Alborz province of Iran. Between January and February 2021, 140 ornamental fish, including 70 sutchi catfish (P. hypophthalmus) and 70 silver dollar (M. hypsauchen), were delivered from various ornamental fish farms for parasitological analysis. Thorough macroscopic and microscopic examinations were performed to detect parasitic infections in delivered freshwater ornamental fish. A total of six parasite species, including five protozoan species (Nyctotherus piscicola, Trichodina heterodentata, Ichthyophthirius multifiliis, Protoopalina sp., and Hexamita sp.) and one monogenean species (Ancyrocephalus sp.), were identified in the examined fish. The overall prevalence of the recovered parasites was 46.43% (65/140) of the fish. In the current study, several parasites, including Hexamita sp., Ancyrocephalus sp., Protoopalina sp., and N. piscicola, were identified as the first records of the sutchi catfish (P. hypophthalmus) and/or silver dollar (M. hypsauchen), and these two fish species are known as new hosts for the isolated parasites in ornamental fish farms in Iran. Assessing the parasitic fauna of ornamental fish is therefore critical for preventing parasite introduction into adjacent provinces as well as neighbouring countries and promoting fish health.

Increased mitochondrial surface area and cristae density in the skeletal muscle of strength athletes.

Mitochondria are the cellular organelles responsible for resynthesising the majority of ATP. In skeletal muscle, there is an increased ATP turnover during resistance exercise to sustain the energetic demands of muscle contraction. Despite this, little is known regarding the mitochondrial characteristics of chronically strength-trained individuals and any potential pathways regulating the strength-specific mitochondrial remodelling. Here, we investigated the mitochondrial structural characteristics in skeletal muscle of strength athletes and age-matched untrained controls. The mitochondrial pool in strength athletes was characterised by increased mitochondrial cristae density, decreased mitochondrial size, and increased surface-to-volume ratio, despite similar mitochondrial volume density. We also provide a fibre-type and compartment-specific assessment of mitochondria morphology in human skeletal muscle, which reveals across groups a compartment-specific influence on mitochondrial morphology that is largely independent of fibre type. Furthermore, we show that resistance exercise leads to signs of mild mitochondrial stress, without an increase in the number of damaged mitochondria. Using publicly available transcriptomic data we show that acute resistance exercise increases the expression of markers of mitochondrial biogenesis, fission and mitochondrial unfolded protein responses (UPRmt ). Further, we observed an enrichment of the UPRmt in the basal transcriptome of strength-trained individuals. Together, these findings show that strength athletes possess a unique mitochondrial remodelling, which minimises the space required for mitochondria. We propose that the concurrent activation of markers of mitochondrial biogenesis and mitochondrial remodelling pathways (fission and UPRmt ) with resistance exercise may be partially responsible for the observed mitochondrial phenotype of strength athletes. KEY POINTS: Untrained individuals and strength athletes possess comparable skeletal muscle mitochondrial volume density. In contrast, strength athletes' mitochondria are characterised by increased cristae density, decreased size and increased surface-to-volume ratio. Type I fibres have an increased number of mitochondrial profiles with minor differences in the mitochondrial morphological characteristics compared with type II fibres. The mitochondrial morphology is distinct across the subcellular compartments in both groups, with subsarcolemmal mitochondria being bigger in size when compared with intermyofibrillar. Acute resistance exercise leads to signs of mild morphological mitochondrial stress accompanied by increased gene expression of markers of mitochondrial biogenesis, fission and mitochondrial unfolded protein response (UPRmt ).

Transcriptional programing of T cell metabolism by STAT family transcription factors.

T cells adapt their metabolism to meet the energetic and biosynthetic demands imposed by changes in location, behavior, and/or differentiation state. Many of these adaptations are controlled by cytokines. Traditionally, research on the metabolic properties of cytokines has focused on downstream signaling via the PI3K-AKT, mTOR, or ERK-MAPK pathways but recent studies indicate that JAK-STAT is also crucial. This review synthesizes current thinking on how JAK-STAT signaling influences T cell metabolism, focusing on adaptations necessary for the naïve, effector, regulatory, memory, and resident-memory states. The overarching theme is that JAK-STAT has both direct and indirect effects. Direct regulation involves STATs localizing to and instructing expression of metabolism-related genes. Indirect regulation involves STATs instructing genes encoding upstream or regulatory factors, including cytokine receptors and other transcription factors, as well as non-canonical JAK-STAT activities. Cytokines impact a vast range of metabolic processes. Here, we focus on those that are most prominent in T cells; lipid, amino acid, and nucleotide synthesis for anabolic metabolism, glycolysis, glutaminolysis, oxidative phosphorylation, and fatty acid oxidation for catabolic metabolism. Ultimately, we advocate the idea that JAK-STAT is a key node in the complex network of signaling inputs and outputs which ensure that T cell metabolism meets lifestyle demands.

Astrocytic aerobic glycolysis provides lactate to support neuronal oxidative metabolism in the hippocampus.

Under physiological conditions, the energetic demand of the brain is met by glucose oxidation. However, ample evidence suggests that lactate produced by astrocytes through aerobic glycolysis may also be an oxidative fuel, highlighting the metabolic compartmentalization between neural cells. Herein, we investigate the roles of glucose and lactate in oxidative metabolism in hippocampal slices, a model that preserves neuron-glia interactions. To this purpose, we used high-resolution respirometry to measure oxygen consumption (O2 flux) at the whole tissue level and amperometric lactate microbiosensors to evaluate the concentration dynamics of extracellular lactate. We found that lactate is produced from glucose and transported to the extracellular space by neural cells in hippocampal tissue. Under resting conditions, endogenous lactate was used by neurons to support oxidative metabolism, which was boosted by exogenously added lactate even in the presence of excess glucose. Depolarization of hippocampal tissue with high K+ significantly increased the rate of oxidative phosphorylation, which was accompanied by a transient decrease in extracellular lactate concentration. Both effects were reverted by inhibition of the neuronal lactate transporter, monocarboxylate transporters 2 (MCT2), supporting the concept of an inward flux of lactate to neurons to fuel oxidative metabolism. We conclude that astrocytes are the main source of extracellular lactate which is used by neurons to fuel oxidative metabolism, both under resting and stimulated conditions.

Aiding Cancer's "Sweet Tooth": Role of Hexokinases in Metabolic Reprogramming.

Hexokinases (HKs) convert hexose sugars to hexose-6-phosphate, thus trapping them inside cells to meet the synthetic and energetic demands. HKs participate in various standard and altered physiological processes, including cancer, primarily through the reprogramming of cellular metabolism. Four canonical HKs have been identified with different expression patterns across tissues. HKs 1-3 play a role in glucose utilization, whereas HK 4 (glucokinase, GCK) also acts as a glucose sensor. Recently, a novel fifth HK, hexokinase domain containing 1 (HKDC1), has been identified, which plays a role in whole-body glucose utilization and insulin sensitivity. Beyond the metabolic functions, HKDC1 is differentially expressed in many forms of human cancer. This review focuses on the role of HKs, particularly HKDC1, in metabolic reprogramming and cancer progression.

Gre factors help Salmonella adapt to oxidative stress by improving transcription elongation and fidelity of metabolic genes.

Detoxification, scavenging, and repair systems embody the archetypical antioxidant defenses of prokaryotic and eukaryotic cells. Metabolic rewiring also aids with the adaptation of bacteria to oxidative stress. Evolutionarily diverse bacteria combat the toxicity of reactive oxygen species (ROS) by actively engaging the stringent response, a stress program that controls many metabolic pathways at the level of transcription initiation via guanosine tetraphosphate and the α-helical DksA protein. Studies herein with Salmonella demonstrate that the interactions of structurally related, but functionally unique, α-helical Gre factors with the secondary channel of RNA polymerase elicit the expression of metabolic signatures that are associated with resistance to oxidative killing. Gre proteins both improve transcriptional fidelity of metabolic genes and resolve pauses in ternary elongation complexes of Embden-Meyerhof-Parnas (EMP) glycolysis and aerobic respiration genes. The Gre-directed utilization of glucose in overflow and aerobic metabolism satisfies the energetic and redox demands of Salmonella, while preventing the occurrence of amino acid bradytrophies. The resolution of transcriptional pauses in EMP glycolysis and aerobic respiration genes by Gre factors safeguards Salmonella from the cytotoxicity of phagocyte NADPH oxidase in the innate host response. In particular, the activation of cytochrome bd protects Salmonella from phagocyte NADPH oxidase-dependent killing by promoting glucose utilization, redox balancing, and energy production. Control of transcription fidelity and elongation by Gre factors represent important points in the regulation of metabolic programs supporting bacterial pathogenesis.

Abstract 4831: Mitochondrial plasticity enables metabolic reprogramming and metastatic latency

Abstract Introduction: Metastatic relapses are common in epidermal growth factor receptor 2 (HER2) amplified breast cancer patients considered disease-free after primary diagnosis and treatment. Stem-like disseminated tumor cells with specialized metastatic traits adapt and survive as latent metastases in distal organs by overcoming oxidative stress, nutrient limitation, microenvironmental and immune defenses. These latent subclinical metastatic cells are responsible for late recurrences. Understanding the traits and vulnerabilities of these cells is critical for developing strategies to prevent metastatic relapse. Method: Here, we employed mouse models and patient samples along with RNA sequencing, Steady-state metabolite analysis, Lipid profiling, C13-isotope tracing, C12-BODIPY pulse chase, Lentiviral shRNA Knockdown, Transmission electron microscopy etc. to investigate how disseminated latent metastatic cells meet their cellular energetic demands and initiate overt metastasis in the lipid-rich brain microenvironment. Result: The ability to utilize available nutrients in distal organs and rewire metabolism is critical for survival of disseminated tumor cells. We report that latent metastatic cells in the brain uptake, store, and utilize fatty acids secreted by tumor-associated reactive astrocytes to meet their cellular energetic needs. Fatty acid oxidation (FAO) and dynamin-related protein 1(DRP1) driven punctate mitochondria enabled utilization of fatty acids and promote survival of latent cells by maintaining cellular bioenergetics and redox homeostasis. Attenuating fatty acid oxidation by genetic and pharmacological inhibition disrupted mitochondrial dynamics and limits metastatic incidence. Likewise, depleting DRP1 altered mitochondrial dynamics that results in reduced FAO, increased reactive oxygen species and attenuated metastatic latency and relapse in HER2+ breast cancer brain metastatic models. Furthermore, comparison with patient-matched primary tumor and brain metastasis identified increased pDRP1 expression in brain metastatic lesions. Moreover, pharmacological inhibition of DRP1 reduced brain metastatic burden in these preclinical models. Conclusion: Despite significant advances in targeted therapies, HER2+ breast cancer patients often develop brain metastasis and their prevention and management remain an unmet need. Our findings in latent HER2+ breast cancer brain metastatic models demonstrate mitochondrial plasticity and altered fatty acid metabolism are key determinants of metastatic adaptation to the brain and establish DRP1 as a promising therapeutic target for treating brain metastasis. Key Words: Breast Cancer Brain Metastasis, Mitochondrial Plasticity, DRP1, Metastatic Latency, Redox Homeostasis. Citation Format: Pravat Kumar Parida, Srinivas Malladi. Mitochondrial plasticity enables metabolic reprogramming and metastatic latency. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4831.

Availability of Supplemental Corn for Sandhill Cranes, Light Geese, and Dabbling Ducks Wintering in New Mexico

Abstract The Middle Rio Grande Valley of central New Mexico overwinters the majority of the Rocky Mountain Population of greater sandhill cranes Antigone canadensis tabida and numerous Midcontinent Population lesser sandhill cranes A. c. canadensis, light geese (i.e., snow Anser caerulescens and Ross's geese Anser rossii), and dabbling ducks (i.e, Anas spp.). Stemming from changes in agricultural practices and loss of habitat, these species have become largely dependent on public lands where corn supplements natural foraging resources, providing a key dietary component while also discouraging crop depredation on private lands. To evaluate if supplemental corn provides a sufficient resource base, we estimated energy available in corn resources and seasonal energy requirements of the sandhill cranes, which consisted of the Rocky Mountain Population and Midcontinent Population. Additionally, we considered energetic requirements for two other wintering guilds, light geese and dabbling ducks. Depletion rates of postmowed corn increased throughout winter from 3,673 ± 843 kg/ha/d (mean ± SE) in December to 7,014 ± 1,884 kg/ha/d in February. The estimated seasonal energetic requirement of the Rocky Mountain Population and Midcontinent Population was 1.14 × 109 kcal (95% CI = 1.07 × 109 to 1.21 × 109 kcal). The combined seasonal energetic demand of the Rocky Mountain Population, Midcontinent Population, light geese, and dabbling ducks was 4.23 × 109 kcal (95% CI = 3.81 × 109 to 4.53 × 109 kcal) or 911,813 kg of corn (95% CI = 820,821–1,006,894 kg). From 2014 to 2017, corn production on public lands in the Middle Rio Grande Valley was 1,052,006 ± 58,965 kg grown on an average of 76 ha, sufficient for winter energetic requirements of all guilds. Interagency collaboration, effective planning during the growing season, and strategic schedules for mowing supplemental corn crops that integrate population abundances and their respective energy demands should further promote success of the supplemental corn program in the Middle Rio Grande Valley.

Abstract 4841: SLC25A46 as a novel mitochondrial regulator and biomarker in breast cancer

Abstract Triple-negative breast cancer (TNBC) is an aggressive, highly malignant breast cancer (BC) subtype further characterized by poor prognosis and chemoresistance. TNBC disproportionately affects African American and Latina women, where the differences in treatment efficacy cannot only be explained by social determinants of health. A better understanding of treatment outcomes requires a deep analysis of the ancestral-related underpinnings that affects treatment. Accounting for the role of ancestry in BC prognosis and progression, we hypothesize that ancestry has significant influences on BC etiology. Metabolic reprogramming of TNBC cells is shown to influence response to treatments. These distinct metabolic adaptations require the proper function of the mitochondrion, a highly dynamic organelle that coordinates and maintains the energetic demands of the cell. To this end, we sought to investigate novel proteins important in mitochondria function yet are understudied in BC phenotypes. SLC25A46 plays a significant role in regulating mitochondrial dynamics, cristae maintenance, and respiratory function. Although SLC25A46 poorly characterized, it has been demonstrated to interact with mitochondrial proteins, such as MFN-2 and OPA1, and the MICOS complex, making it an attractive pharmacological target. We were therefore interested if SLC25A46 has any potential as a target or biomarker in BC. First, we applied PrediXcan, a gene-based statistical algorithm, to calculate genetically predicted gene expression for SLC25A46 in 70,349 patients of European descent and 14,462 patients of African descent in BioVU, the Vanderbilt University Medical Center (VUMC) biorepository linked to de-identified electronic health records (EHRs). Models were built using RNA-seq data from the publicly available GTEX version 8 dataset. After fitting a multivariable logistic regression model to test SLC25A46 predicted expression against 1,704 phenotypes for each tissue, we observed that patients with high predicted expression were more likely to receive diagnosis of ‘abnormal findings in mammograms’ (P=2.76E-06, OR=2.26) or ‘lump or mass in breast’ (P=8.9E-06, OR=2.61) in the European descent group, which is well powered; however, we are not powered to replicate this finding in the African descent group. Therefore, we investigated SLC25A46 expression in an international RNAseq cohort enriched with women of African ancestry, including African Americans (AA), West and East Africans with TNBC (n=26). Interestingly, SLC25A46 shows significantly higher expression among self-reported AA than Ghanaian or Ethiopian women with TNBC (P=0.003). Thus, we postulated that these differences in SLC25A46 for patients of African ancestry might serve as a novel biomarker for cancer outcomes. Together, these data suggest that SLC25A46 has implications in BC as a novel target in cancer development, specifically in patients with admixed ancestry. Citation Format: Heather K. Beasley, Ky'Era V. Actkins, Tyne Miller-Flemming, Nancy J. Cox, Rachel Martini, Melissa B. Davis, Timothy Chu, Nicolas Robine, Bret C. Mobley, Antentor O. Hinton. SLC25A46 as a novel mitochondrial regulator and biomarker in breast cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4841.

Abstract 3209: Metabolic characterization of radiation-induced cardiotoxicity

Abstract Background: Approximately 50% of all cancer patients receive radiation therapy as a component of their cancer care. While radiation therapy has demonstrable benefit in improving survival in patients, radiation-induced heart disease (RIHD) is a major contributor to morbidity and mortality in cancer survivors with history of thoracic radiation. Understanding metabolic changes underlying RIHD may enable development of novel diagnostic and therapeutic approaches for early detection and treatment of RIHD. The high energetic demands of the heart require properly functioning mitochondria to meet the ATP production needs. Fatty acids are the primary metabolic substrates for energy production in a healthy heart. However, under conditions of stress, the cardiac metabolism shifts towards increased glucose utilization. In this study, we characterize the impact of radiation of cardiac substrate utilization and energy production. Methods: Pre-clinical RIHD models were established by administering whole heart radiation (8Gy x 5) in mice and rats followed by structural and biochemical characterization. Transmission electron microscopy and western blot analyses were used to characterize structural and biochemical changes in the heart in response to radiation. Spectrophotometric assays and Western blot analyses were used to characterize changes in pyruvate dehydrogenase (PDH) activity and function in the heart in response to radiation. Results: Our studies identified myocardial mitochondrial dysfunction as an early event following exposure of heart to radiation. Cardiac irradiation resulted in increased mitochondrial fusion and higher expression of MFN1, a key protein that mediates mitochondrial fusion. The pathological structural and biochemical changes in the myocardial mitochondria are associated with reduced glucose metabolism due to impaired PDH activity. This decline was mediated by increased phosphorylation of PDH in irradiated hearts, which inhibits its activity. Conclusion: Cardiac irradiation results in early metabolic dysregulation, especially in glucose metabolism, which may be exploited for early detection and mitigation of radiation-induced cardiotoxicity. Citation Format: Sarah C. Elliott, Jayesh Sharma, Elizabeth R. Zhang-Velten, Abdallah Elnwasany, Chantal Vidal, Luke Szweda, Prasanna Alluri. Metabolic characterization of radiation-induced cardiotoxicity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3209.

How scaling approaches can reveal fundamental principles in physiology and biomechanics

Among terrestrial mammals, the largest, the 3tonne African elephant, is one-million times heavier than the smallest, the 3g pygmy shrew. Body mass is the most obvious and arguably the most fundamental characteristic of an animal, impacting many important attributes of its life history and biology. Although evolution may guide animals to different sizes, shapes, energetic profiles or ecological niches, it is the laws of physics that limit biological processes and, in turn, affect how animals interact with their environment. Consideration of scaling helps us to understand why elephants are not merely scaled-up shrews, but rather have modified body proportions, posture and locomotor style to mitigate the consequences of their large size. Scaling offers a quantitative lens into how biological features vary compared with predictions based on physical laws. In this Review, we provide an introduction to scaling and its historical context, focusing on two fields that are strongly represented in experimental biology: physiology and biomechanics. We show how scaling has been used to explore metabolic energy use with changes in body size. We discuss the musculoskeletal and biomechanical adaptations that animals use to mitigate the consequences of size, and provide insights into the scaling of mechanical and energetic demands of animal locomotion. For each field, we discuss empirical measurements, fundamental scaling theories and the importance of considering phylogenetic relationships when performing scaling analyses. Finally, we provide forward-looking perspectives focused on improving our understanding of the diversity of form and function in relation to size.

Regulation of neuronal energy metabolism by calcium: Role of MCU and Aralar/malate-aspartate shuttle

Calcium is a major regulator of cellular metabolism. Calcium controls mitochondrial respiration, and calcium signaling is used to meet cellular energetic demands through energy production in the organelle. Although it has been widely assumed that Ca2+-actions require its uptake by mitochondrial calcium uniporter (MCU), alternative pathways modulated by cytosolic Ca2+ have been recently proposed. Recent findings have indicated a role for cytosolic Ca2+ signals acting on mitochondrial NADH shuttles in the control of cellular metabolism in neurons using glucose as fuel. It has been demonstrated that AGC1/Aralar, the component of the malate/aspartate shuttle (MAS) regulated by cytosolic Ca2+, participates in the maintenance of basal respiration exerted through Ca2+-fluxes between ER and mitochondria, whereas mitochondrial Ca2+-uptake by MCU does not contribute. Aralar/MAS pathway, activated by small cytosolic Ca2+ signals, provides in fact substrates, redox equivalents and pyruvate, fueling respiration. Upon activation and increases in workload, neurons upregulate OxPhos, cytosolic pyruvate production and glycolysis, together with glucose uptake, in a Ca2+-dependent way, and part of this upregulation is via Ca2+ signaling. Both MCU and Aralar/MAS contribute to OxPhos upregulation, Aralar/MAS playing a major role, especially at small and submaximal workloads. Ca2+ activation of Aralar/MAS, by increasing cytosolic NAD+/NADH provides Ca2+-dependent increases in glycolysis and cytosolic pyruvate production priming respiration as a feed-forward mechanism in response to workload. Thus, except for glucose uptake, these processes are dependent on Aralar/MAS, whereas MCU is the relevant target for Ca2+ signaling when MAS is bypassed, by using pyruvate or β-hydroxybutyrate as substrates.

Between fruits, flowers and nectar: The extraordinary diet of the frog Xenohyla truncata

Pollination and seed dispersal are determinants for plant survivorship. Among land vertebrates, mammals and birds stand out in these relationships with plants. On the other hand, frogs are not expected to play a role in these interactions, as nearly all species are carnivorous (mostly insectivorous) after metamorphosis. However, one species attracts attention: Xenohyla truncata, which includes plant parts on its natural diet. Recently, we observed unexpected interactions between this Neotropical treefrog and plants in their native range. The frog fed on different plant parts, consuming fruits, floral structures and nectar with suction-like movements, and we observed pollen grains adhered to the frog's back, which renders this treefrog as a potential pollinator, besides its already established role as seed disperser. Nectar ingestion during the reproductive season could benefit individuals under high energetic demand. This is a unique and outstanding example of unforeseen interactions between amphibians and plants.

'I just don't trust my pelvic floor': Examining the bio-social barriers to maternal health and physical activity participation in a sample of mothers' from New Zealand

Maternal physical activity participation is associated with a range of positive mental and physical health outcomes. While a range of psycho-social and practical barriers to women's participation have been identified, little research has examined how these intersect with the physiological barriers posed by birthing injuries and the physical changes wrought by pregnancy and childbirth. In this study we address this gap using data collected through in-depth interviews with 20 women in Aotearoa New Zealand seeking to engage in regular exercise following childbirth. Guided by a socio-material conceptual framework, we examine women's physical activity engagement as bio-social phenomena. We pay particular attention to how women describe and navigate challenges posed by physiological considerations such as pelvic floor dysfunction, fatigue, the energetic demands of breastfeeding, and lingering birthing injuries. We argue these physical barriers are largely glossed over by policies, programmes and existing research that focus on motivating mothers to return to or become physically active. We suggest more sophisticated conceptual approaches are needed that explicitly acknowledge the overlapping biological and social dimensions of maternal physical activity in order to better support women through the complex postpartum period and beyond through enhanced resources, information, and general social awareness.

Amino acids in hematologic malignancies: Current status and future perspective.

In recent years, growing emphasis has been placed on amino acids and their role in hematologic malignancies. Cancer cell metabolism is altered during tumorigenesis and development to meet expanding energetic and biosynthetic demands. Amino acids not only act as energy-supplying substances, but also play a vital role via regulating key signaling pathways, modulating epigenetic factors and remodeling tumor microenvironment. Targeting amino acids may be an effective therapeutic approach to address the current therapeutic challenges. Here, we provide an updated overview of mechanisms by which amino acids facilitate tumor development and therapy resistance. We also summarize novel therapies targeting amino acids, focusing on recent advances in basic research and their potential clinical implications.

Sertoli cell adaptation to glucose deprivation: Potential role of AMPK in the regulation of lipid metabolism.

Sertoli cells (SCs) provide an adequate environment for germ cell development. SCs possess unique features that meet germ cells' metabolic demands: they produce lactate from glucose, which is delivered as energy substrate to germ cells. SCs store fatty acids (FAs) as triacylglycerols (TAGs) in lipid droplets (LDs) and can oxidize FAs to sustain their own energetic demands. They also produce ketone bodies from FAs. It has been shown that exposure of SCs to metabolic stresses, such as glucose deprivation, triggers specific adaptive responses that sustain cell survival and preserve lactate supply to germ cells. The aim of the present study was to investigate whether there are modifications in rat SCs lipid metabolism, including LD content, FA oxidation, and ketone bodies production, as part of their adaptive response to glucose deprivation. The present study was performed in 20-day-old rat SCs cultures. We determined LD content by Oil Red O staining, FA oxidation by measuring the release of 3 H2 O from [3 H] palmitate, TAGs and 3-hydroxybutyrate levels by spectrophotometric methods, and mRNA levels by RT-qPCR. Results show that the absence of glucose in SC culture medium entails: (1) a decrease in LD content and TAGs levels that is accompanied by decreased perilipin 1 mRNA levels, (2) an increase in FA oxidation that is in part mediated by AMP kinase (AMPK) activation and (3) a decrease in 3-hydroxybutyrate production. Additionally, we studied whether sestrins (SESN1, 2 and 3), proteins involved in the cellular response to stress, are regulated in glucose deprivation conditions. We show that there is an increase in SESN2 mRNA levels in deprived conditions. In conclusion, glucose deprivation affects SC lipid metabolism promoting FA mobilization from LDs to be used as energy source.

Cellular and environmental dynamics influence species-specific extents of organelle gene retention.

Mitochondria and plastids rely on many nuclear-encoded genes, but retain small subsets of the genes they need to function in their own organelle DNA (oDNA). Different species retain different numbers of oDNA genes, and the reasons for these differences are not completely understood. Here, we use a mathematical model to explore the hypothesis that the energetic demands imposed by an organism's changing environment influence how many oDNA genes it retains. The model couples the physical biology of cell processes of gene expression and transport to a supply-and-demand model for the environmental dynamics to which an organism is exposed. The trade-off between fulfilling metabolic and bioenergetic environmental demands, and retaining genetic integrity, is quantified for a generic gene encoded either in oDNA or in nuclear DNA. Species in environments with high-amplitude, intermediate-frequency oscillations are predicted to retain the most organelle genes, whereas those in less dynamic or noisy environments the fewest. We discuss support for, and insight from, these predictions with oDNA data across eukaryotic taxa, including high oDNA gene counts in sessile organisms exposed to day-night and intertidal oscillations (including plants and algae) and low counts in parasites and fungi.