Exercise metabolism and adaptation in skeletal muscle.

Viewing metabolism through the lens of exercise biology has proven an accessible and practical strategy to gain new insights into local and systemic metabolic regulation. Recent methodological developments have advanced understanding of the central role of skeletal muscle in many exercise-associated health benefits and have uncovered the molecular underpinnings driving adaptive responses to training regimens. In this Review, we provide a contemporary view of the metabolic flexibility and functional plasticity of skeletal muscle in response to exercise. First, we provide background on the macrostructure and ultrastructure of skeletal muscle fibres, highlighting the current understanding of sarcomeric networks and mitochondrial subpopulations. Next, we discuss acute exercise skeletal muscle metabolism and the signalling, transcriptional and epigenetic regulation of adaptations to exercise training. We address knowledge gaps throughout and propose future directions for the field. This Review contextualizes recent research of skeletal muscle exercise metabolism, framing further advances and translation into practice.

The Biology of Physiological Health.

The ability to maintain health, or recover to a healthy state after disease, is an active process involving distinct adaptation mechanisms coordinating interactions between all physiological systems of an organism. Studies over the past several decades have assumed the mechanisms of health and disease are essentially inter-changeable, focusing on the elucidation of the mechanisms of disease pathogenesis to enhance health, treat disease, and increase healthspan. Here, I propose that the evolved mechanisms of health are distinct from disease pathogenesis mechanisms and suggest that we develop an understanding of the biology of physiological health. In this Perspective, I provide a definition of, a conceptual framework for, and proposed mechanisms of physiological health to complement our understanding of disease and its treatment.

Mechanisms of mitochondrial respiratory adaptation.

Mitochondrial energetic adaptations encompass a plethora of conserved processes that maintain cell and organismal fitness and survival in the changing environment by adjusting the respiratory capacity of mitochondria. These mitochondrial responses are governed by general principles of regulatory biology exemplified by changes in gene expression, protein translation, protein complex formation, transmembrane transport, enzymatic activities and metabolite levels. These changes can promote mitochondrial biogenesis and membrane dynamics that in turn support mitochondrial respiration. The main regulatory components of mitochondrial energetic adaptation include: the transcription coactivator peroxisome proliferator-activated receptor-γ (PPARγ) coactivator 1α (PGC1α) and associated transcription factors; mTOR and endoplasmic reticulum stress signalling; TOM70-dependent mitochondrial protein import; the cristae remodelling factors, including mitochondrial contact site and cristae organizing system (MICOS) and OPA1; lipid remodelling; and the assembly and metabolite-dependent regulation of respiratory complexes. These adaptive molecular and structural mechanisms increase respiration to maintain basic processes specific to cell types and tissues. Failure to execute these regulatory responses causes cell damage and inflammation or senescence, compromising cell survival and the ability to adapt to energetically demanding conditions. Thus, mitochondrial adaptive cellular processes are important for physiological responses, including to nutrient availability, temperature and physical activity, and their failure leads to diseases associated with mitochondrial dysfunction such as metabolic and age-associated diseases and cancer.

Human Immunology through the Lens of Evolutionary Genetics.

Pathogen-imposed selection pressures have been paramount during human evolution. Detecting such selection signatures in ancient and modern human genomes can thus help us to identify genes of temporal and spatial immunological relevance. Admixture with ancient hominins and between human populations has been a source of genetic diversity open to selection by infections. Furthermore, cultural transitions, such as the advent of agriculture, have exposed humans to new microbial threats, with impacts on host defense mechanisms. The integration of population genetics and systems immunology holds great promise for the increased understanding of the factors driving immune response variation between individuals and populations.

Adaptation in auditory processing.

Adaptation is an essential feature of auditory neurons, which reduces their responses to unchanging and recurring sounds and allows their response properties to be matched to the constantly changing statistics of sounds that reach the ears. As a consequence, processing in the auditory system highlights novel or unpredictable sounds and produces an efficient representation of the vast range of sounds that animals can perceive by continually adjusting the sensitivity and, to a lesser extent, the tuning properties of neurons to the most commonly encountered stimulus values. Together with attentional modulation, adaptation to sound statistics also helps to generate neural representations of sound that are tolerant to background noise and therefore plays a vital role in auditory scene analysis. In this review, we consider the diverse forms of adaptation that are found in the auditory system in terms of the processing levels at which they arise, the underlying neural mechanisms, and their impact on neural coding and perception. We also ask what the dynamics of adaptation, which can occur over multiple timescales, reveal about the statistical properties of the environment. Finally, we examine how adaptation to sound statistics is influenced by learning and experience and changes as a result of aging and hearing loss.

Molecular responses to acute exercise and their relevance for adaptations in skeletal muscle to exercise training.

Repeated, episodic bouts of skeletal muscle contraction undertaken frequently as structured exercise training are a potent stimulus for physiological adaptation in many organs. Specifically, in skeletal muscle, remarkable plasticity is demonstrated by the remodeling of muscle structure and function in terms of muscular size, force, endurance, and contractile velocity as a result of the functional demands induced by various types of exercise training. This plasticity, and the mechanistic basis for adaptations to skeletal muscle in response to exercise training, are underpinned by activation and/or repression of molecular pathways and processes in response to each individual acute exercise session. These pathways include the transduction of signals arising from neuronal, mechanical, metabolic, and hormonal stimuli through complex signal transduction networks, which are linked to a myriad of effector proteins involved in the regulation of pre- and posttranscriptional processes, and protein translation and degradation processes. This review therefore describes acute exercise-induced signal transduction and the molecular responses to acute exercise in skeletal muscle including emerging concepts such as epigenetic pre- and posttranscriptional regulation and the regulation of protein translation and degradation. A critical appraisal of methodological approaches and the current state of knowledge informs a series of recommendations offered as future directions in the field.

Selective loss of resident macrophage-derived insulin-like growth factor-1 abolishes adaptive cardiac growth to stress.

Hypertension affects one-third of the world's population, leading to cardiac dysfunction that is modulated by resident and recruited immune cells. Cardiomyocyte growth and increased cardiac mass are essential to withstand hypertensive stress; however, whether immune cells are involved in this compensatory cardioprotective process is unclear. In normotensive animals, single-cell transcriptomics of fate-mapped self-renewing cardiac resident macrophages (RMs) revealed transcriptionally diverse cell states with a core repertoire of reparative gene programs, including high expression of insulin-like growth factor-1 (Igf1). Hypertension drove selective in situ proliferation and transcriptional activation of some cardiac RM states, directly correlating with increased cardiomyocyte growth. During hypertension, inducible ablation of RMs or selective deletion of RM-derived Igf1 prevented adaptive cardiomyocyte growth, and cardiac mass failed to increase, which led to cardiac dysfunction. Single-cell transcriptomics identified a conserved IGF1-expressing macrophage subpopulation in human cardiomyopathy. Here we defined the absolute requirement of RM-produced IGF-1 in cardiac adaptation to hypertension.

Widespread Prion-Based Control of Growth and Differentiation Strategies in Saccharomyces cerevisiae.

Theory and experiments suggest that organisms would benefit from pre-adaptation to future stressors based on reproducible environmental fluctuations experienced by their ancestors, but the mechanisms driving pre-adaptation remain enigmatic. We report that the [SMAUG+] prion allows yeast to anticipate nutrient repletion after periods of starvation, providing a strong selective advantage. By transforming the landscape of post-transcriptional gene expression, [SMAUG+] regulates the decision between two broad growth and survival strategies: mitotic proliferation or meiotic differentiation into a stress-resistant state. [SMAUG+] is common in laboratory yeast strains, where standard propagation practice produces regular cycles of nutrient scarcity followed by repletion. Distinct [SMAUG+] variants are also widespread in wild yeast isolates from multiple niches, establishing that prion polymorphs can be utilized in natural populations. Our data provide a striking example of how protein-based epigenetic switches, hidden in plain sight, can establish a transgenerational memory that integrates adaptive prediction into developmental decisions.

Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity.

Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. How metabolism is implicated in specific phenotypes and whether lineage-restricted mechanisms control key metabolic vulnerabilities remain poorly understood. In melanoma, downregulation of the lineage addiction oncogene microphthalmia-associated transcription factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, although how MITF promotes proliferation and suppresses invasion is poorly defined. Here, we show that MITF is a lineage-restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD) and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signaling, and an ATF4-mediated feedback loop that maintains de-differentiation. Our results reveal that MITF is a lineage-specific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype switching, and highlight that cell phenotype dictates the response to drugs targeting lipid metabolism.

SHRED Is a Regulatory Cascade that Reprograms Ubr1 Substrate Specificity for Enhanced Protein Quality Control during Stress.

When faced with proteotoxic stress, cells mount adaptive responses to eliminate aberrant proteins. Adaptive responses increase the expression of protein folding and degradation factors to enhance the cellular quality control machinery. However, it is unclear whether and how this augmented machinery acquires new activities during stress. Here, we uncover a regulatory cascade in budding yeast that consists of the hydrophilin protein Roq1/Yjl144w, the HtrA-type protease Ynm3/Nma111, and the ubiquitin ligase Ubr1. Various stresses stimulate ROQ1 transcription. The Roq1 protein is cleaved by Ynm3. Cleaved Roq1 interacts with Ubr1, transforming its substrate specificity. Altered substrate recognition by Ubr1 accelerates proteasomal degradation of misfolded as well as native proteins at the endoplasmic reticulum membrane and in the cytosol. We term this pathway stress-induced homeostatically regulated protein degradation (SHRED) and propose that it promotes physiological adaptation by reprogramming a key component of the quality control machinery.

Distinct early and late neural mechanisms regulate feature-specific sensory adaptation in the human visual system.

A canonical feature of sensory systems is that they adapt to prolonged or repeated inputs, suggesting the brain encodes the temporal context in which stimuli are embedded. Sensory adaptation has been observed in the central nervous systems of many animal species, using techniques sensitive to a broad range of spatiotemporal scales of neural activity. Two competing models have been proposed to account for the phenomenon. One assumes that adaptation reflects reduced neuronal sensitivity to sensory inputs over time (the "fatigue" account); the other posits that adaptation arises due to increased neuronal selectivity (the "sharpening" account). To adjudicate between these accounts, we exploited the well-known "tilt aftereffect", which reflects adaptation to orientation information in visual stimuli. We recorded whole-brain activity with millisecond precision from human observers as they viewed oriented gratings before and after adaptation, and used inverted encoding modeling to characterize feature-specific neural responses. We found that both fatigue and sharpening mechanisms contribute to the tilt aftereffect, but that they operate at different points in the sensory processing cascade to produce qualitatively distinct outcomes. Specifically, fatigue operates during the initial stages of processing, consistent with tonic inhibition of feedforward responses, whereas sharpening occurs ~200 ms later, consistent with feedback or local recurrent activity. Our findings reconcile two major accounts of sensory adaptation, and reveal how this canonical process optimizes the detection of change in sensory inputs through efficient neural coding.

AMPK and the Adaptation to Exercise.

Noncommunicable diseases are chronic diseases that contribute to death worldwide, but these diseases can be prevented and mitigated with regular exercise. Exercise activates signaling molecules and the transcriptional network to promote physiological adaptations, such as fiber type transformation, angiogenesis, and mitochondrial biogenesis. AMP-activated protein kinase (AMPK) is a master regulator that senses the energy state, promotes metabolism for glucose and fatty acid utilization, and mediates beneficial cellular adaptations in many vital tissues and organs. This review focuses on the current, integrative understanding of the role of exercise-induced activation of AMPK in the regulation of system metabolism and promotion of health benefits.

PP2B-Dependent Cerebellar Plasticity Sets the Amplitude of the Vestibulo-ocular Reflex during Juvenile Development.

Throughout life, the cerebellum plays a central role in the coordination and optimization of movements, using cellular plasticity to adapt a range of behaviors. Whether these plasticity processes establish a fixed setpoint during development, or continuously adjust behaviors throughout life, is currently unclear. Here, by spatiotemporally manipulating the activity of protein phosphatase 2B (PP2B), an enzyme critical for cerebellar plasticity in male and female mice, we examined the consequences of disrupted plasticity on the performance and adaptation of the vestibulo-ocular reflex (VOR). We find that, in contrast to Purkinje cell (PC)-specific deletion starting early postnatally, acute pharmacological as well as adult-onset genetic deletion of PP2B affects all forms of VOR adaptation but not the level of VOR itself. Next, we show that PC-specific genetic deletion of PP2B in juvenile mice leads to a progressive loss of the protein PP2B and a concurrent change in the VOR, in addition to the loss of adaptive abilities. Finally, re-expressing PP2B in adult mice that lack PP2B expression from early development rescues VOR adaptation but does not affect the performance of the reflex. Together, our results indicate that chronic or acute, genetic, or pharmacological block of PP2B disrupts the adaptation of the VOR. In contrast, only the absence of plasticity during cerebellar development affects the setpoint of VOR, an effect that cannot be corrected after maturation of the cerebellum. These findings suggest that PP2B-dependent cerebellar plasticity is required during a specific period to achieve the correct setpoint of the VOR.

Transient changes to metabolic homeostasis initiate mitochondrial adaptation to endurance exercise.

Endurance exercise is well established to increase mitochondrial content and function in skeletal muscle, a process termed mitochondrial biogenesis. Current understanding is that exercise initiates skeletal muscle mitochondrial remodeling via modulation of cellular nutrient, energetic and contractile stress pathways. These subtle changes in the cellular milieu are sensed by numerous transduction pathways that serve to initiate and coordinate an increase in mitochondrial gene transcription and translation. The result of these acute signaling events is the promotion of growth and assembly of mitochondria, coupled to a greater capacity for aerobic ATP provision in skeletal muscle. The aim of this review is to highlight the acute metabolic events induced by endurance exercise and the subsequent molecular pathways that sense this transient change in cellular homeostasis to drive mitochondrial adaptation and remodeling.

The outstanding capacity of Prasiola antarctica to thrive in contrasting harsh environments relies on the constitutive protection of thylakoids and on morphological plasticity.

The determination of physiological tolerance ranges of photosynthetic species and of the biochemical mechanisms underneath are fundamental to identify target processes and metabolites that will inspire enhanced plant management and production for the future. In this context, the terrestrial green algae within the genus Prasiola represent ideal models due to their success in harsh environments (polar tundras) and their extraordinary ecological plasticity. Here we focus on the outstanding Prasiola antarctica and compare two natural populations living in very contrasting microenvironments in Antarctica: the dry sandy substrate of a beach and the rocky bed of an ephemeral freshwater stream. Specifically, we assessed their photosynthetic performance at different temperatures, reporting for the first time gnsd values in algae and changes in thylakoid metabolites in response to extreme desiccation. Stream population showed lower α-tocopherol content and thicker cell walls and thus, lower gnsd and photosynthesis. Both populations had high temperatures for optimal photosynthesis (around +20°C) and strong constitutive tolerance to freezing and desiccation. This tolerance seems to be related to the high constitutive levels of xanthophylls and of the cylindrical lipids di- and tri-galactosyldiacylglycerol in thylakoids, very likely related to the effective protection and stability of membranes. Overall, P. antarctica shows a complex battery of constitutive and plastic protective mechanisms that enable it to thrive under harsh conditions and to acclimate to very contrasting microenvironments, respectively. Some of these anatomical and biochemical adaptations may partially limit photosynthesis, but this has a great potential to rise in a context of increasing temperature.

Surface Sensing and Adaptation in Bacteria.

Bacteria thrive both in liquids and attached to surfaces. The concentration of bacteria on surfaces is generally much higher than in the surrounding environment, offering bacteria ample opportunity for mutualistic, symbiotic, and pathogenic interactions. To efficiently populate surfaces, they have evolved mechanisms to sense mechanical or chemical cues upon contact with solid substrata. This is of particular importance for pathogens that interact with host tissue surfaces. In this review we discuss how bacteria are able to sense surfaces and how they use this information to adapt their physiology and behavior to this new environment. We first survey mechanosensing and chemosensing mechanisms and outline how specific macromolecular structures can inform bacteria about surfaces. We then discuss how mechanical cues are converted to biochemical signals to activate specific cellular processes in a defined chronological order and describe the role of two key second messengers, c-di-GMP and cAMP, in this process.

Evolutionary systems biology reveals patterns of rice adaptation to drought-prone agro-ecosystems.

Rice (Oryza sativa) was domesticated around 10,000 years ago and has developed into a staple for half of humanity. The crop evolved and is currently grown in stably wet and intermittently dry agro-ecosystems, but patterns of adaptation to differences in water availability remain poorly understood. While previous field studies have evaluated plant developmental adaptations to water deficit, adaptive variation in functional and hydraulic components, particularly in relation to gene expression, has received less attention. Here, we take an evolutionary systems biology approach to characterize adaptive drought resistance traits across roots and shoots. We find that rice harbors heritable variation in molecular, physiological, and morphological traits that is linked to higher fitness under drought. We identify modules of co-expressed genes that are associated with adaptive drought avoidance and tolerance mechanisms. These expression modules showed evidence of polygenic adaptation in rice subgroups harboring accessions that evolved in drought-prone agro-ecosystems. Fitness-linked expression patterns allowed us to identify the drought-adaptive nature of optimizing photosynthesis and interactions with arbuscular mycorrhizal fungi. Taken together, our study provides an unprecedented, integrative view of rice adaptation to water-limited field conditions.

Repeated sprint training in hypoxia induces specific skeletal muscle adaptations through S100A protein signaling.

Athletes increasingly engage in repeated sprint training consisting in repeated short all-out efforts interspersed by short recoveries. When performed in hypoxia (RSH), it may lead to greater training effects than in normoxia (RSN); however, the underlying molecular mechanisms remain unclear. This study aimed at elucidating the effects of RSH on skeletal muscle metabolic adaptations as compared to RSN. Sixteen healthy young men performed nine repeated sprint training sessions in either normoxia (FIO2 = 0.209, RSN, n = 7) or normobaric hypoxia (FIO2 = 0.136, RSH, n = 9). Before and after the training period, exercise performance was assessed by using repeated sprint ability (RSA) and Wingate tests. Vastus lateralis muscle biopsies were performed to investigate muscle metabolic adaptations using proteomics combined with western blot analysis. Similar improvements were observed in RSA and Wingate tests in both RSN and RSH groups. At the muscle level, RSN and RSH reduced oxidative phosphorylation protein content but triggered an increase in mitochondrial biogenesis proteins. Proteomics showed an increase in several S100A family proteins in the RSH group, among which S100A13 most strongly. We confirmed a significant increase in S100A13 protein by western blot in RSH, which was associated with increased Akt phosphorylation and its downstream targets regulating protein synthesis. Altogether our data indicate that RSH may activate an S100A/Akt pathway to trigger specific adaptations as compared to RSN.

Perturbation Variability Does Not Influence Implicit Sensorimotor Adaptation.

Implicit adaptation has been regarded as a rigid process that automatically operates in response to movement errors to keep the sensorimotor system precisely calibrated. This hypothesis has been challenged by recent evidence suggesting flexibility in this learning process. One compelling line of evidence comes from work suggesting that this form of learning is context-dependent, with the rate of learning modulated by error history. Specifically, learning was attenuated in the presence of perturbations exhibiting high variance compared to when the perturbation is fixed. However, these findings are confounded by the fact that the adaptation system corrects for errors of different magnitudes in a non-linear manner, with the adaptive response increasing in a proportional manner to small errors and saturating to large errors. Through simulations, we show that this non-linear motor correction function is sufficient to explain the effect of perturbation variance without referring to an experience-dependent change in error sensitivity. Moreover, by controlling the distribution of errors experienced during training, we provide empirical evidence showing that there is no measurable effect of perturbation variance on implicit adaptation. As such, we argue that the evidence to date remains consistent with the rigidity assumption.

The tuning of tuning: How adaptation influences single cell information transfer.

Sensory neurons reconstruct the world from action potentials (spikes) impinging on them. To effectively transfer information about the stimulus to the next processing level, a neuron needs to be able to adapt its working range to the properties of the stimulus. Here, we focus on the intrinsic neural properties that influence information transfer in cortical neurons and how tightly their properties need to be tuned to the stimulus statistics for them to be effective. We start by measuring the intrinsic information encoding properties of putative excitatory and inhibitory neurons in L2/3 of the mouse barrel cortex. Excitatory neurons show high thresholds and strong adaptation, making them fire sparsely and resulting in a strong compression of information, whereas inhibitory neurons that favour fast spiking transfer more information. Next, we turn to computational modelling and ask how two properties influence information transfer: 1) spike-frequency adaptation and 2) the shape of the IV-curve. We find that a subthreshold (but not threshold) adaptation, the 'h-current', and a properly tuned leak conductance can increase the information transfer of a neuron, whereas threshold adaptation can increase its working range. Finally, we verify the effect of the IV-curve slope in our experimental recordings and show that excitatory neurons form a more heterogeneous population than inhibitory neurons. These relationships between intrinsic neural features and neural coding that had not been quantified before will aid computational, theoretical and systems neuroscientists in understanding how neuronal populations can alter their coding properties, such as through the impact of neuromodulators. Why the variability of intrinsic properties of excitatory neurons is larger than that of inhibitory ones is an exciting question, for which future research is needed.