bioRxiv - Physiology最新文献

{"title":"Dissecting the metabolic costs of up- and down-hill walking","authors":"Luke N Jessup, Luke A Kelly, Andrew G Cresswell, Glen A Lichtwark","doi":"10.1101/2024.08.08.607266","DOIUrl":"https://doi.org/10.1101/2024.08.08.607266","url":null,"abstract":"Work- and collision-based models of locomotion are often used to describe the relationship between the mechanical work requirements of the body and metabolic energy expenditure. While work- and collision-based models do a reasonable job of relating mechanical work to metabolic cost at a system level, these models may not map to the underlying force and work demands of muscle, which directly affects energy expenditure. We collected motion capture, force, electromyography and ultrasound data from the main power producing muscles during uphill and downhill walking between +/- 15% grade. These data were used to evaluate a musculoskeletal modelling approach to simulate muscle force- and work-related costs that could be compared to metabolic power that we measured using indirect calorimetry. Muscle force-related costs (activation heat rate + maintenance heat rate) increased at steeper up- and down-hill grades and were moderately correlated with mean joint moments. Muscle work-related costs (mechanical work rate + shortening / lengthening heat rate) increased as grade became more positive and were strongly correlated with net joint work. Compared to traditional models, the inclusion of a term to account for muscle force-related costs should lead to a more explanatory cost model that maps directly to the mechanical demands of muscle.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"158 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933476","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Massive reduction of RyR1 in muscle spindles of mice carrying recessive Ryr1 mutations alters proprioception and causes scoliosis","authors":"Alexis Ruiz, Sofia Benucci, Herve Meier, Georg Schultz, Katarzyna Buczak, Christoph Handschin, Rodrigo C. G. Pena, Susan Treves, Francesco Zorzato","doi":"10.1101/2024.08.09.607317","DOIUrl":"https://doi.org/10.1101/2024.08.09.607317","url":null,"abstract":"Muscle spindles are stretch receptors lying deep within the muscle belly involved in detecting changes in muscle length and playing a fundamental role in motor control, posture and synchronized gait. They are made up of an external capsule surrounding 3-5 intrafusal muscle fibers and a nuclear bag complex. Dysfunction of muscle spindles leads to abnormal proprioceptor function, which has been linked to aberrant bone and cartilage development, scoliosis, kyphosis and joint contractures. RYR1, the gene encoding the calcium release channel of the sarcoplasmic reticulum, is the most common target of mutations linked to human congenital myopathies, a condition often accompanied by skeleton alterations and joint contractures. So far, the link between RYR1 mutations, altered muscle spindles and skeletal defects has not been investigated. To this end, we investigated heterozygous mice carrying recessive Ryr1 mutations isogenic to those present in a severely affected child. Here we show that: (i) the RyR1 protein localizes to the polar regions of intrafusal fibers and exhibits a doubled row distribution pattern, typical for junctional sarcoplasmic reticulum proteins; (ii) muscle spindles of compound heterozygous mice show structural defects; (iii) RyR1 content in intrafusal muscle fibers from dHT mice is reduced by 54%. Such a massive reduction of mutant RyR1 in intrafusal muscle fibers leads to altered expression of intrafusal fiber proteins, severe scoliosis, alteration of gait and inter limb coordination. These results support the hypothesis that RYR1 mutations not only affect the function of extrafusal muscles, but might also affect that of intrafusal muscles. The latter may be one of the underlying causes of skeletal abnormalities seen in patients affected by recessive RYR1 mutations.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"76 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933474","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ophthalmic acid is a bloodborne metabolite that contributes to age-induced cardiomyocyte hypertrophy","authors":"Melod Mehdipour, Sangsoon Park, Wei Wei, Jonathan Z Long, Guo N. Huang","doi":"10.1101/2024.08.08.607218","DOIUrl":"https://doi.org/10.1101/2024.08.08.607218","url":null,"abstract":"Cardiac aging involves the development of left ventricular hypertrophy alongside a decline in functional capacity. Here, we use neutral blood exchange to demonstrate that the acute removal of age-accumulated blood factors significantly regresses cardiac hypertrophy in aged mice. The reversal of hypertrophy was not attributed to age-associated hemodynamic effects, implicating a role of blood-derived factors. In addition, the overarching paradigm of systemic aging maintains that the age-related overabundance of plasma proteins are largely responsible for causing pathological phenotypes in tissues. Our results suggest that blood metabolites, not proteins, drive cardiac hypertrophy instead. Upon analyzing serum metabolomics data sets, we identified ophthalmic acid as a circulating metabolite whose levels increase with advanced age. Treatment of adult mouse and neonatal rat cardiomyocytes in culture with ophthalmic acid increased their relative surface areas. This study uncovers a non-protein metabolite that may contribute to cardiomyocyte hypertrophy during aging. Identifying a method to counteract the hypertrophic effect of ophthalmic acid may reveal novel therapeutic opportunities for cardiac rejuvenation.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On the rate-limiting dynamics of force development in muscle","authors":"Tim J van der Zee, Jeremy D Wong, Arthur D Kuo","doi":"10.1101/2024.08.07.606988","DOIUrl":"https://doi.org/10.1101/2024.08.07.606988","url":null,"abstract":"Skeletal muscles produce forces relatively slowly compared to the action potentials that excite them. The dynamics of force production are governed by multiple processes, such as calcium activation, cycling of crossbridges between myofilaments, and contraction against elastic tissues and the body. These processes have been included piecemeal in some muscle models, but not integrated to reveal which are the most rate limiting. We therefore examined their integrative contributions to force development in two conventional types of muscle models - Hill-type and crossbridge. We found that no combination of these processes can self-consistently reproduce classic data such as twitch and tetanus. Rather, additional dynamics are needed following calcium activation and facilitating crossbridge cycling, such as for cooperative myofilament interaction and reconfiguration. We provisionally lump such processes into a simple first-order model of \"force facilitation dynamics\" that integrate into a crossbridge-type muscle model. The proposed model self-consistently reproduces force development for a range of excitations including twitch and tetanus and electromyography-to-force curves. The model's step response reveals relatively small timing contributions of calcium activation (3%), crossbridge cycling (3%), and contraction (27%) to overall force development of human quadriceps, with a remainder (67%) explained by force facilitation. The same set of model parameters predicts the change in force magnitude (gain) and timing (phase delay) as a function of excitatory firing rate, or as a function of cyclic contraction frequency. Although experiments are necessary to reveal the dynamics of muscle, integrative models are useful for identifying the main rate-limiting processes.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cysteine depletion triggers adipose tissue thermogenesis and weight-loss","authors":"Aileen H. Lee, Lucie Orliaguet, Yun-Hee Youm, Rae Maeda, Tamara Dlugos, Yuanjiu Lei, Daniel Coman, Irina Shchukina, Sairam Andhey, Steven R. Smith, Eric Ravussin, Krisztian Stadler, Fahmeed Hyder, Maxim N. Artyomov, Yuki Sugiura, Vishwa Deep Dixit","doi":"10.1101/2024.08.06.606880","DOIUrl":"https://doi.org/10.1101/2024.08.06.606880","url":null,"abstract":"Dietary interventions such as caloric restriction (CR)¹ and methionine restriction² that prolong lifespan induce the ‘browning’ of white adipose tissue (WAT), an adaptive metabolic response that increases heat production to maintain health^3,4. However, how diet influences adipose browning and metabolic health is unclear. Here, we identified that weight-loss induced by CR in humans⁵ reduces cysteine concentration in WAT suggesting depletion of this amino-acid may be involved in metabolic benefits of CR. To investigate the role of cysteine on organismal metabolism, we created a cysteine-deficiency mouse model in which dietary cysteine was eliminated and cystathionine γ-lyase (CTH)⁶, the enzyme that synthesizes cysteine was conditionally deleted. Using this animal model, we found that systemic cysteine-depletion causes drastic weight-loss with increased fat utilization and browning of adipose tissue. The restoration of dietary cysteine in cysteine-deficient mice rescued weight loss together with reversal of adipose browning and increased food-intake in an on-demand fashion. Mechanistically, cysteine deficiency induced browning and weight loss is dependent on sympathetic nervous system derived noradrenaline signaling via β3-adrenergic-receptors and does not require UCP1. Therapeutically, in high-fat diet fed obese mice, one week of cysteine-deficiency caused 30% weight-loss and reversed inflammation. These findings thus establish that cysteine is essential for organismal metabolism as removal of cysteine in the host triggers adipose browning and rapid weight loss.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"105 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933550","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prenatal Dexamethasone Programs Autonomic Dysregulation in Female Rats","authors":"Lakshmi Madhavpeddi, Monique Martinez, Jared Alvarez, Arpan Sharma, Chengcheng Hu, Stuart A Tobet, Taben M Hale","doi":"10.1101/2024.08.05.606452","DOIUrl":"https://doi.org/10.1101/2024.08.05.606452","url":null,"abstract":"Autonomic dysfunction is associated with cardiovascular and neurological disease, including hypertension, heart failure, anxiety, and stress-related disorders. Prior studies demonstrated that late gestation exposure to dexamethasone (DEX) resulted in female-biased increases in stress-responsive mean arterial pressure (MAP) and heart rate (HR), suggesting a role for glucocorticoid-mediated programming of autonomic dysfunction. The present study investigated the influence of sympathetic (SYM) or parasympathetic (PS) blockade on cardiovascular function in male and female rat offspring of mothers injected with DEX <em>in utero</em> (gestation days [GD]18-21). At 11-12-weeks of age, MAP, HR, and heart rate variability (HRV) were evaluated at baseline and in response to SYM antagonists (α₁-adrenoceptor + β₁-adrenoceptor), a PS (muscarinic) antagonist, or saline (SAL). To assess stress-responsive function, rats were exposed to acute restraint. Tyrosine hydroxylase was measured in adrenals and left ventricle, and gene expression for the β₁ adrenergic receptor was measured in left ventricle. Maternal DEX injection reduced basal HRV in male and female offspring. SYM blockade attenuated increases in stress-responsive HR and MAP. PS blockade elevated stress-responsive HR and MAP to a greater extent in Vehicle females. SYM and PS blockade produced equivalent effects on HR and MAP responses in male offspring, regardless of maternal treatment. Based on these findings, we suggest that maternal DEX injection disrupted autonomic regulation of cardiovascular function in females, resulting in a shift toward greater SYM input and less input from PS. Future studies will investigate whether changes in autonomic function are mediated by changes in central autonomic circuitry.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Regulation of Ferroptosis in Obesity: Muscle Type-Specific Effects of Dietary Restriction and Exercise","authors":"Fujue Ji, Yu Jin Park, Haesung Lee, Jong-Hee Kim","doi":"10.1101/2024.08.04.605473","DOIUrl":"https://doi.org/10.1101/2024.08.04.605473","url":null,"abstract":"<strong>Background</strong> Obesity is a significant global health issue and a risk factor for numerous diseases. Ferroptosis, an iron-dependent regulated cell death, is triggered by iron overload and the excessive accumulation of lipid peroxidation mediated by reactive oxygen species. Studies has identified a strong association between ferroptosis and obesity. Additionally, dietary restriction (DR) and DR combined with exercise (DR+Ex) are effective strategies for managing obesity and ferroptosis. However, the regulation of ferroptosis and its signaling pathways in skeletal muscle under conditions of obesity, DR, and DR+Ex remains poorly understood.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A preliminary investigation into the effects of a soluble dietary fibre and mineral formulation on post-prandial glucose regulation and satiation in healthy adults","authors":"Michael M Haynes","doi":"10.1101/2024.08.03.606479","DOIUrl":"https://doi.org/10.1101/2024.08.03.606479","url":null,"abstract":"Prevalence of obesity and overweight has steadily increased over the past decade, urging the development, and refining of various methods of intervention to combat the epidemic. Glucomannan is a dietary fibre with gelling properties, contributing to satiety. Chromium picolinate is an artificial additive, initially suggested to be an essential trace element, contributing to lipid and carbohydrate metabolism. Fructo-oligosaccharides are among a group of calorie free prebiotics, contributing to mineral absorption. Here, we are presenting an open label, preliminary investigation, to explore the effect of a formulation containing glucomannan, chromium picolinate and fructo-oligosaccharides on post-prandial blood glucose modulation and hunger and satiation in 17 adults (Mean ± SD: age 26.35 ± 5.18 years; height 171 ± 11.22 cm; body weight 73.24 ± 13.23 kg; BMI 24.89 ± 2.72 kg/m²). Data have shown significant reductions in feelings of hunger (P = &gt; .001), and desire to eat (P= &gt; .001), with no significant effect on blood glucose control. These findings have suggested use of this formulation in dietary intervention, through controlling obesity related parameters.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"10 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933555","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"RF Channel-Based Adaptive Beamforming for 3D Ultrasound Localization Microscopy","authors":"Georges Chabouh, Baptiste Pialot, Louise Denis, Raphael Dumas, Olivier Couture, Pauline Muleki Seya, François Varray","doi":"10.1101/2024.08.02.606290","DOIUrl":"https://doi.org/10.1101/2024.08.02.606290","url":null,"abstract":"Ultrasound Localization Microscopy (ULM) has been applied in various preclinical settings and in the clinic to reveal the microvasculature in deep organs. However, most ULM images employ standard Delay-and-Sum (DAS) beamforming. In standard ULM conditions, lengthy acquisition times are required to fully reconstruct small vessels due to the need for spatially isolated microbubbles, resulting in low temporal resolution. When microbubbles are densely packed, localizing a point spread function with significant main and side lobes becomes challenging due to matrix arrays’ low signal-to-noise ratio and spatial resolution. In this work, we applied adaptive beamforming such as high order DAS known as (pDAS), Coherence Factor (CF), Coherence Factor with Gaussian Filtering (CFGF), and statistical interpretation of beamforming (iMAP) to provide a more complete 3D ULM maps <em>in vitro</em> and <em>in vivo</em> (rat kidney). Specifically, the CF and 1MAP adaptive beamformers achieved higher resolution (32.9 microns and 27.2 microns respectively), as measured by the Fourier Shell Correlation (FSC), compared to the standard DAS beamformer, which had an FSC value of 38.6 microns.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"304 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Paradoxical SERCA dysregulation contributes to atrial fibrillation in a model of diet-induced obesity","authors":"Daniela Ponce-Balbuena, Daniel J. Tyrrell, Carlos Cruz-Cortés, Guadalupe Guerrero-Serna, Andre Monteiro Da Rocha, Todd J. Herron, Jianrui Song, Danyal S. Raza, Justus Anumonwo, Daniel R. Goldstein, L. Michel Espinoza-Fonseca","doi":"10.1101/2024.08.02.606385","DOIUrl":"https://doi.org/10.1101/2024.08.02.606385","url":null,"abstract":"Obesity is a major risk factor for atrial fibrillation (AF) the most common serious cardiac arrhythmia, but the molecular mechanisms underlying diet-induced AF remain unclear. In this study, we subjected mice to a chronic high-fat diet and acute sympathetic activation (‘two-hit’ model) to study the mechanisms by which diet-induced obesity promotes AF. Surface electrocardiography revealed that diet-induced obesity and sympathetic activation synergize during intracardiac tachypacing to induce AF. At the cellular level, diet-induced obesity and acute adrenergic stimulation facilitate the formation of delayed afterdepolarizations in atrial myocytes, implicating altered Ca²⁺ dynamics as the underlying cause of AF. We found that diet-induced obesity does not alter the expression of major Ca²⁺-handling proteins in atria, including the sarcoplasmic reticulum Ca²⁺-ATPase (SERCA), a major component of beat-to-beat Ca²⁺ cycling in the heart. Paradoxically, obesity reduces phospholamban phosphorylation, suggesting decreased SERCA activity, yet atrial myocytes from obese mice showed a significantly increased Ca²⁺ transient amplitude and SERCA-mediated Ca²⁺ uptake. Adrenergic stimulation further increases the Ca²⁺ transient amplitude but does not affect Ca²⁺ reuptake in atrial myocytes from obese mice. Transcriptomics analysis showed that a high-fat diet prompts upregulation of neuronatin, a protein that has been implicated in obesity and is known to stimulate SERCA activity. We propose a mechanism in which obesity primes SERCA for paradoxical activation, and adrenergic stimulation facilitates AF conversion through a Ca²⁺-induced Ca²⁺ release gain in atrial myocytes. Overall, this study links obesity, altered Ca²⁺ signaling, and AF, and targeting this mechanism may prove effective for treating obesity-induced AF.","PeriodicalId":501557,"journal":{"name":"bioRxiv - Physiology","volume":"158 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141933608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}