Muller DC, Boeno FP, Reis G
… +7 more, Azam A, Ashley M, Zhou Y, Yue F, Ryan TE, Efron PA, Laitano O
Acta Physiol (Oxf)
· 2026 Apr · PMID 41849194
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BACKGROUND: Sepsis is associated with skeletal muscle weakness and atrophy, particularly in older and immobilized patients; however, how sepsis interacts with disuse, reloading, aging, and biological sex remains poorly d...BACKGROUND: Sepsis is associated with skeletal muscle weakness and atrophy, particularly in older and immobilized patients; however, how sepsis interacts with disuse, reloading, aging, and biological sex remains poorly defined. METHODS: Young (5 mo) and older (20 mo) male and female C57BL/6J mice underwent cecal ligation and puncture (CLP) or sham surgery followed by hindlimb suspension (HLS) or normal ambulation (NA) for 7 days (Experiment 1). A separate cohort underwent 3 days of reloading after HLS (REL; Experiment 2). Outcomes included survival, body mass, soleus force-frequency, myofiber cross-sectional area (CSA), macrophage infiltration (CD68), extracellular matrix (ECM), and satellite cells (Pax7). RESULTS: Survival was preserved in septic young mice (> 84%) but reduced in older septic mice (~51%-60% males; ~57% females). Disuse was the primary driver of body mass loss during HLS/REL, with older females exhibiting the greatest decline (day 11: -19.8% ± 6.8% Sham; -17.4% ± 6.5% CLP). Disuse reduced median fiber CSA by ~27%-46% across cohorts (e.g., young males: 1840 ± 189 to 997 ± 345 μm). In Experiment 1, CD68 macrophages increased most with combined sepsis and disuse, whereas ECM expansion was observed only in males. Pax7 satellite cells were markedly reduced in young males with sepsis and disuse and in older mice of both sexes with sepsis. Following REL, older septic males retained force deficits, and septic females remained significantly atrophic. CONCLUSION: Muscle disuse amplifies sepsis-induced myopathy in an age- and sex-dependent manner, with incomplete early recovery after reloading.
Cardani S, Janes TA, Asif R
… +1 more, Pagliardini S
Acta Physiol (Oxf)
· 2026 Apr · PMID 41823358
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AIM: Rhythmic breathing movements driven by the brainstem rely on chemosensory inputs to homeostatically adjust motor output to the prevailing metabolic demand. The central CO chemoreflex is a critical component of this...AIM: Rhythmic breathing movements driven by the brainstem rely on chemosensory inputs to homeostatically adjust motor output to the prevailing metabolic demand. The central CO chemoreflex is a critical component of this neural circuitry, as defects in these sensors cause hypoventilation syndromes, which are typically difficult to manage pharmacologically. Progesterone has long been known to stimulate breathing in both sexes, and remarkably the progestinic metabolite, etonogestrel (ETO), enhances CO chemosensitivity in animal models and female patients affected by congenital central hypoventilation syndrome. However, ETO's mechanisms and sites of action remain unknown, and the experimental use of synthetic progestins has been met with mixed respiratory outcomes. METHODS: In our recent work, we demonstrated that chronic ETO treatment improved the CO chemoreflex in female rats in which < 80% of chemoreceptor neurons comprising the retrotrapezoid nucleus (RTN) were eliminated. Since the progesterone receptor is widely expressed in both the male and female brain, we investigated whether ETO-induced CO chemoreflex recovery can be replicated in male rats in which RTN neurons are partially eliminated by the use of substance P-saporin toxin. RESULTS: Our results confirm dose-dependent impairment of the CO chemoreflex in both sexes following chemoreceptor lesion and corroborate the findings that ETO treatment restores ventilation in female rats with moderate-sized lesions. Interestingly, female respiratory recovery was associated with increased expression of the pH-sensing genes Gpr4 and Task2 in the RTN. CONCLUSION: In contrast, male rats failed to show significant recovery with ETO treatment, suggesting a sex-specific mechanism through which ETO promotes CO chemoreflex recovery.
Fei L, Wang X, Kong L
… +21 more, Cui T, Khedkar PH, Xiang Y, Zhao D, Fang J, Liang Y, Zhang Y, Xu N, Qiu X, Zhao L, Zhang G, Lei Y, Tang C, Ma K, Lu L, Wei J, Lai EY, Persson PB, Patzak A, Zheng Z, Jiang S
Acta Physiol (Oxf)
· 2026 Apr · PMID 41814130
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AIM: Calcineurin inhibitors (CNI) such as tacrolimus (Tac) are the first-line treatment to prevent transplant rejection. However, CNI have adverse effects on blood vessels and renal function, which may be linked to cellu...AIM: Calcineurin inhibitors (CNI) such as tacrolimus (Tac) are the first-line treatment to prevent transplant rejection. However, CNI have adverse effects on blood vessels and renal function, which may be linked to cellular senescence. Valsartan, a common angiotensin II type 1 receptor (ATR) blocker, exhibits anti-senescence properties. We tested the hypothesis that tacrolimus causes hypertension and microvascular remodeling that involves induction of senescence, and that valsartan is protective. METHODS: Microperfusion and wire myography were employed to assess the contractile and dilatory functions of renal afferent arterioles (Af-Art) and mesenteric arteries, respectively. The expression of components of the renin-angiotensin system (RAS) and senescence-associated biomarkers was investigated using qPCR and immunohistochemistry. RESULTS: Long-term administration of Tac activated the RAS. Tac-induced microvascular remodeling in mesenteric arteries and Af-Art was mitigated by treatment with valsartan. Mice treated with Tac exhibited increased vasoconstriction in response to angiotensin II and reduced dilation to acetylcholine. Both effects were abolished by valsartan. Additionally, senescence-associated biomarkers were upregulated in mesenteric and renal resistance arteries from Tac-treated mice. Co-administration of Tac with valsartan or ABT-263, a senolytic agent, rescued Tac-induced microvascular injury and reduced hypertension (conscious mice, noninvasive tail-cuff system). Treatment with the antihypertensive drug amlodipine normalized blood pressure and downregulated senescence-associated beta-galactosidase in mesenteric arteries. CONCLUSION: These findings suggest that cellular senescence contributes to Tac-induced microvascular injury and hypertension and demonstrate the effectiveness of senolytic treatment for protection. Valsartan could reduce senescence indirectly by lowering blood pressure; a direct anti-senescence effect might also play a role in this context.
Luque NM, Leader L, Lowe SM
… +9 more, Horrowitz SD, Tare M, Hinkley V, Matchkov VV, Costantine MM, Markus I, Liu L, Sandow SL, Murphy TV
Acta Physiol (Oxf)
· 2026 Apr · PMID 41808442
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AIM: Endothelium-dependent relaxation in isolated uterine radial arteries from normotensive (NT) and preeclamptic (PE) pregnancies, and the acute effects of pravastatin in the latter vessels were assessed. Pravastatin is...AIM: Endothelium-dependent relaxation in isolated uterine radial arteries from normotensive (NT) and preeclamptic (PE) pregnancies, and the acute effects of pravastatin in the latter vessels were assessed. Pravastatin is hypothesized to alleviate endothelial dysfunction in PE via modulating aspects of NO and endothelium-derived hyperpolarization-mediated relaxation. METHODS: Radial arteries isolated from the uterus of NT and PE pregnant patients were incubated with pravastatin (2 mM/6 h), methyl-β-cyclodextrin (10 mM/1 h) in vitro, or vehicle. Vessel function was determined with pressure myography, while related morphology and protein/mRNA expression were characterized using immunohistochemistry, electron microscopy, and qPCR. RESULTS: Endothelium-dependent, bradykinin-induced NO-mediated relaxation was impaired in radial arteries from PE compared to NT pregnancy, with a reduced intermediate- and large-conductance Ca-activated K-channel contribution. Endothelial small-conductance Ca-activated K-channel function and expression were increased in arteries from PE, compared to NT patients. Pravastatin restored NO and endothelium-derived hyperpolarization-mediated relaxation in arteries from PE women; potentially overcompensating overall endothelium-dependent relaxation. Myoendothelial gap junction and endothelial caveolae density, and caveolin-1 and endothelial-NOS expression were decreased in arteries from PE relative to NT pregnancies and increased following pravastatin incubation. Caveolae density in NT patient arteries was reduced by methyl-β-cyclodextrin, while endothelial caveolae were increased in vessels from PE patients. Pravastatin incubation restored endothelial function via improved NO and endothelium-derived hyperpolarization-type mechanisms. CONCLUSIONS: Pravastatin restored endothelium-dependent relaxation in uterine radial arteries from PE pregnancies. Data support the therapeutic potential for pravastatin in treating PE, with ongoing trials determining the validity of its use in the clinical setting. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01717586.
AIM: Excessive fructose consumption is strongly linked to metabolic syndrome. Dietary fructose is predominantly transported into cells through the solute carrier family 2 member 5 and/or member 2, and then metabolized by...AIM: Excessive fructose consumption is strongly linked to metabolic syndrome. Dietary fructose is predominantly transported into cells through the solute carrier family 2 member 5 and/or member 2, and then metabolized by fructokinase (also known as ketohexokinase, KHK), which is primarily expressed in the intestine, liver, and kidney. The significant contribution of KHK-mediated fructose metabolism in the intestine or liver to sugar-induced metabolic syndrome has been well documented. This study aimed to elucidate the pathophysiological significance of renal KHK-mediated fructose metabolism in the pathogenesis of fructose-induced metabolic syndrome. METHODS: A mouse model with inducible deletion of both KHK isoforms (KHK-A and KHK-C) in renal tubules was generated using the Cre-LoxP recombination system. We then systematically evaluated parameters associated with fructose-induced metabolic syndrome in these mice fed a 20% fructose solution (w/v). RESULTS: In mice receiving excess fructose solutions, the inducible deletion of KHK via the Pax8-rtTA/LC1 system entirely blocks fructose metabolism and is sufficient to prevent the development of metabolic syndrome. The latter is evidenced by improved glucose and insulin resistance, alleviated hepatic steatosis and liver injury, mitigated adipose tissue remodeling, and strengthened colonic epithelial barrier integrity in fructose-fed Khk-deficient mice. These protections are likely attributed to the reduced uric acid generation resulting from the blockade of fructose metabolism. CONCLUSION: Our findings suggest that KHK-mediated fructose metabolism in the kidneys may be crucial for the development of fructose-induced metabolic syndrome.
Acta Physiol (Oxf)
· 2026 Apr · PMID 41782211
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AIM: Reduced placental mTOR signaling is associated with intrauterine growth restriction and impaired maternal and placental metabolism. Since maternal hypothyroidism induces intrauterine growth restriction, and maternal...AIM: Reduced placental mTOR signaling is associated with intrauterine growth restriction and impaired maternal and placental metabolism. Since maternal hypothyroidism induces intrauterine growth restriction, and maternal treatment with kisspeptin-10 (Kp10) has been shown to improve feto-placental development in hypothyroid rats, this study aimed to evaluate the effects of maternal hypothyroidism, with and without kisspeptin-10 treatment, on maternal energy homeostasis and placental expression of mTOR and glucose metabolism mediators. METHODS: Maternal hypothyroidism was induced by administration of propylthiouracil, and kisspeptin-10 treatment began on gestational day 8. RESULTS: Maternal hypothyroidism caused glucose intolerance, decreased insulin and HDL levels, reduced fetal and placental weights, and thinned the placental interhaemal barrier. It also increased INSRβ and AKT, while downregulating placental p-mTOR/mTOR and Glut1. Although kisspeptin-10 treatment did not improve maternal glucose homeostasis or prevent feto-placental growth restriction, it attenuated maternal hypothyroidism-induced placental Glut1 dysregulation, upregulated the IGF1/IGF1R axis, and restored placental AKT/mTOR expression. CONCLUSION: These findings suggest that kisspeptin-10 treatment in hypothyroid pregnant rats improves placental mTOR signaling and glucose metabolism mediators, highlighting novel pathways through which kisspeptin may modulate placental physiology.
Schwab A, Rugi M, Swietach P
… +35 more, Błaszczak W, Novak I, Deshar G, Pedersen SF, Ialchina R, Sandelin A, Yao J, Reshkin SJ, Cardone RA, Carvalho TMA, Arcangeli A, Bouazzi R, D'Alessandro FN, Prevarskaya N, Audero MM, Ouadid-Ahidouch H, Schnipper J, Pardo LA, Shi X, Alves F, Mitręga J, Trauzold A, Hagelund SE, Panyi G, Cozzolino M, Löwik CMWG, Mezzanotte L, McMorrow R, Pahl A, Hechler T, Papacharisi E, Pla AF, Szabo I, Hofschröer V, Pethő Z
Acta Physiol (Oxf)
· 2026 Apr · PMID 41755693
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AIM: Pancreatic ductal adenocarcinoma (PDAC) develops within a uniquely dynamic pH landscape shaped by substantial acid-base fluxes produced by the exocrine pancreas. Secretion of alkaline pancreatic juice, normally link...AIM: Pancreatic ductal adenocarcinoma (PDAC) develops within a uniquely dynamic pH landscape shaped by substantial acid-base fluxes produced by the exocrine pancreas. Secretion of alkaline pancreatic juice, normally linked to digestion, produces intermittent acidifications of the pancreatic interstitium, which challenges epithelial and stromal cells. It was postulated that these unique pancreatic pH dynamics can facilitate PDAC initiation and progression through selection of a more aggressive phenotype emerging with PDAC driver mutations. METHODS: Here, we summarize evidence that pH-regulatory transport proteins have an important role in shaping the PDAC microenvironment. RESULTS: pH-regulatory transport proteins generate and sense their microenvironment and act as signaling hubs to regulate proliferation, migration, and metabolism, and immune evasion. In this way, transport proteins that are crucial for the normal physiology of the exocrine pancreas are misused and become coerced into playing a pro-cancer role in pancreatic tumor cells, pancreatic stellate cells, or infiltrating immune cells. Experiments with PDAC mouse models revealed a therapeutic potential of targeting pH dynamics, notably by inhibition or genetic ablation of pH-regulatory proteins. It is a consistent finding that these maneuvers have a marked impact on the tumor immune defense and the communication between cancer and immune cells. CONCLUSION: Collectively, we present a case for considering pH-regulating proteins as a therapeutic avenue.
Bergouignan A, Noone J, Brun C
… +11 more, Cussonneau L, Geffroy A, Coudy-Gandilhon C, Chery I, Evans AL, Arnemo JM, Kindberg J, Gauquelin-Koch G, O'Gorman D, Lefai E, Bertile F
Acta Physiol (Oxf)
· 2026 Apr · PMID 41725390
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AIM: Unlike humans, brown bears (Ursus arctos) uniquely preserve skeletal muscle mass and function during months of hibernation despite prolonged fasting and inactivity. We investigated how mitochondrial energetics respo...AIM: Unlike humans, brown bears (Ursus arctos) uniquely preserve skeletal muscle mass and function during months of hibernation despite prolonged fasting and inactivity. We investigated how mitochondrial energetics respond in skeletal muscle to support this remarkable resilience. METHODS: Muscle biopsies from eight wild brown bears were collected during hibernation and again in the active summer season. We assessed mitochondrial respiration using high-resolution respirometry and evaluated changes in protein expression, enzyme activity, and mitochondrial content through proteomics, Western blotting, enzymatic assays, and DNA quantification. RESULTS: Hibernation was associated with lower mitochondrial respiratory capacity, largely due to a reduction in mitochondrial density rather than damage or dysfunction. Despite reduced SDH subunit expression in the whole skeletal muscle, SDH activity remained stable. This likely reflects post-translational regulation and increased, or at least maintained, functional efficiency of the remaining Complex II, allowing mitochondrial respiration to shift toward Complex II-mediated electron entry during hibernation. Proteomic analyses revealed targeted adjustments that maintained energy efficiency, supported both fat and carbohydrate oxidation at low temperatures, and minimized energy loss. Additionally, selective downregulation of mitochondrial dynamic proteins may help protect against muscle degradation. CONCLUSION: These findings highlight a temperature-sensitive, multifaceted strategy that preserves mitochondrial energetics during prolonged inactivity, despite reduced mitochondrial density. The selective maintenance of electron flow and fuel flexibility offers novel insights for mitigating muscle wasting in sedentary or immobilized humans.