American Journal Of Physiology. Cell Physiology[JOURNAL]
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200 papers
Effects of proANP in a preclinical model of uninephrectomy and cardiac ischemia/reperfusion injury: cardiac remodeling and tissue biochemical profiling.
Silva GJJ, Stefani S, Parvan R … +13 more , Frisk M, Shen X, Alunni Cardinali M, Strand ME, Rypdal KB, Stokke MK, Attramadal H, Lunde IG, Aronsen JM, Stensløkken KO, Louch WE, Sassi P, Cataliotti A
Am J Physiol Cell Physiol · 2026 May · PMID 41830464 · Publisher ↗
Concomitant cardiac and renal dysfunction represent a clinically relevant condition with limited therapeutic options. This study examined the effects of the linear ANP fragment proANP in a preclinical model combining uni...
Concomitant cardiac and renal dysfunction represent a clinically relevant condition with limited therapeutic options. This study examined the effects of the linear ANP fragment proANP in a preclinical model combining unilateral nephrectomy (UNX) and cardiac ischemia/reperfusion (I/R) injury. Wistar rats underwent UNX followed by I/R and were randomized to receive proANP or vehicle for 4 wk. Cardiac structure and function were evaluated by echocardiography and isolated cardiomyocyte analyses. Fourier-transform infrared (FTIR) spectroscopy was used to assess biochemical composition in cardiac and renal tissue, as well as urine. Chronic UNX induced diastolic impairment with preserved systolic function, which was further aggravated by I/R. ProANP prevented systolic deterioration, reduced myocardial fibrosis, attenuated cardiomyocyte hypertrophy, and improved Ca handling, independent of blood pressure. FTIR imaging identified distinct cardiac (amino acid-, collagen-, and carbohydrate-associated) and renal (free amino acid-, protein-, and lipid-associated) spectral features across experimental groups. Conventional renal indices, including albumin-to-creatinine ratio and 24 h protein excretion, remained unchanged; however, vibrational spectroscopy detected subtle biochemical alterations in renal tissue and urine that were modulated by proANP. In this model of reduced nephron mass with superimposed cardiac injury, proANP exerted marked cardioprotective effects and was associated with coordinated changes in tissue biochemical signatures, supporting further investigation of its therapeutic potential. In a model of reduced nephron mass combined with cardiac ischemia/reperfusion injury, proANP prevented adverse cardiac remodeling independent of blood pressure. Vibrational spectroscopy identified coordinated biochemical alterations in cardiac and renal tissues not detected by conventional assays, providing molecular-level insight into cardiorenal remodeling.
Flavin adenine dinucleotide increases antioxidant availability and protects neonatal C57Bl6 lungs from high oxygen induced lung injury.
Montgomery HD, Zhang MA, Zimmerman E … +1 more , Helms MN
Am J Physiol Cell Physiol · 2026 Apr · PMID 41811728 · Full text
Therapeutic interventions effective in reestablishing redox homeostasis in preterm infants require further investigation because immature lungs are extremely vulnerable to high-oxygen-induced lung injury. Flavin adenine...
Therapeutic interventions effective in reestablishing redox homeostasis in preterm infants require further investigation because immature lungs are extremely vulnerable to high-oxygen-induced lung injury. Flavin adenine dinucleotide (FAD) facilitates glutathione reductase (GR) activity and increases the bioavailability of the antioxidant glutathione (GSH). As such, we hypothesize that intranasal delivery of FAD can attenuate hyperoxic lung injury by restoring redox homeostasis, thereby altering pro-inflammatory signal transduction pathways. The term C57Bl6/N mouse model exposed to 0.85 fraction of inspired oxygen (85% [Formula: see text]) was used to model high oxygen-induced oxidative stress and bronchopulmonary dysplasia (BPD). Our studies show that FAD protects neonatal lungs (males and females) from high oxygen-induced oxidative stress by improving GSH/oxidized glutathione (GSSG) redox potential () from -168.77 mV ± 3.64 mV to -179.10 mV ± 1.85 mV; measured in bronchoalveolar lavage fluid (BALF). FAD also improved lung injury scores from 0.047 ± 0.007 to 0.007 ± 0.004 ( < 0.001), decreased neutrophil migration ( < 0.001), and increased macrophages in BALF ( < 0.001) when compared with age-matched vehicle-treated pups similarly housed at 85% [Formula: see text]. Cytokine profiling revealed that FAD treatment significantly enhanced the secretion of multiple interleukin family cytokines under hyperoxic conditions relative to both room air and untreated 85% [Formula: see text] control groups. In particular, IL-12p70, IL-27, IL-6, and IL-1α were markedly elevated, suggesting that FAD modulates inflammatory signaling pathways activated during oxidative stress. Collectively, these findings indicate that FAD treatment modulates inflammatory signaling pathways activated during hyperoxia, potentially contributing to cellular adaptation or protection. Our findings support a conceptual shift in neonatal antioxidant therapy. Using a mouse model of preterm lungs and high oxygen-induced oxidative stress, we found that intranasal delivery of flavin adenine dinucleotide (FAD) improved newborn lung health. FAD restored redox balance, reduced neutrophilia, and modulated cytokines associated with lung development and repair.
Chasing the ghost in the code: highlighting the mystery of a rare genetic condition.
Delpire E
Am J Physiol Cell Physiol · 2026 May · PMID 41811711 · Full text
Here, we recount the story of a remarkable young girl who demonstrated extraordinary courage and resilience while confronting significant health challenges over the span of 23 years. Her journey is a testament to her det...
Here, we recount the story of a remarkable young girl who demonstrated extraordinary courage and resilience while confronting significant health challenges over the span of 23 years. Her journey is a testament to her determination to survive and thrive despite overwhelming obstacles. We detail the investigative efforts aimed at associating her clinical symptoms with a specific membrane transporter: the Na-K-2Cl cotransporter-1 (NKCC1), which this laboratory has dedicated more than three decades to studying. The work summarized here covers experiments using patient-derived cells, cells engineered to express wild-type or mutant cotransporter, and genetically modified mice carrying this patient-specific alteration. It is illuminated by reports of other rare human deleterious mutations, and work done by us and others using NKCC1 knockout mouse models. During our studies, we uncovered details regarding the trafficking of NKCC1, shedding light on how the protein is transported and positioned to carry out its function in epithelial cells. Furthermore, our findings revealed that NKCC1 may play a role in energy metabolism, suggesting that its activity influences metabolic processes within affected tissues. Our investigations also underscored the involvement of NKCC1 in the development of the nervous system. In addition, we discuss the evidence found that intestinal dysfunction is linked to NKCC1 abnormalities and evidence showing an established link between the cotransporter and epithelial cell-mediated inflammation. This patient's story stands as a testament to perseverance and the importance of scientific inquiry in understanding rare genetic disorders.
Distinct P2 receptors initiate intracellular signaling involved in mechanotransduction in tenocytes.
Armstrong RE, Khan MN, Grol MW
Am J Physiol Cell Physiol · 2026 May · PMID 41811693 · Publisher ↗
Tendons adapt to mechanical load through mechanotransduction, but the molecular mechanisms underlying this process have not been fully elucidated. In other musculoskeletal tissues, purinergic (P2) receptors-activated by...
Tendons adapt to mechanical load through mechanotransduction, but the molecular mechanisms underlying this process have not been fully elucidated. In other musculoskeletal tissues, purinergic (P2) receptors-activated by extracellular nucleotides released during mechanical stress-are critical regulators of cellular responses. Here, we investigated whether similar P2 signaling pathways are present in tendons. We show that primary tenocytes express several P2 receptors, including P2X4, P2Y, and P2Y. Live-cell imaging revealed that both ATP and UTP trigger transient intracellular calcium (Ca) signaling via P2Y. Surprisingly, only ATP significantly increased expression of mechanosensitive cytokines [interleukin 6 (), prostaglandin-endoperoxide synthase 2 ()] and the tendon-specific transcription factor scleraxis (), suggesting that additional P2 receptors contribute to ATP-driven gene regulation. Using bulk RNA-sequencing (RNA-seq), we performed the first unbiased, genome-wide analysis of early transcriptional responses to extracellular nucleotide stimulation in tenocytes. Transcriptomic profiling revealed that ATP selectively activates gene programs linked to inflammation and immune responses, whereas both ATP and UTP regulate genes associated with cell differentiation, angiogenesis, metabolism, and responses to mechanical stimuli. Consistent with these findings, receptor-specific inhibition demonstrated that P2Y and P2X4 both contribute to ATP-induced transcriptional changes, whereas broader P2 receptor inhibition completely abrogated ATP-driven gene expression, supporting redundant or convergent purinergic signaling in tenocytes. Together, these findings suggest that while P2Y governs calcium dynamics, the broader purinergic signaling network, including P2Y, P2X4, and possibly others, serves as a central mediator of tenocyte mechanotransduction. This study shows that appendicular and axial tenocytes express P2 receptors, including P2Y, P2Y, and P2X4. Nucleotides signal through Ca via P2Y, while several P2 receptors, including P2Y and P2X4, trigger transcriptome changes that influence inflammation, differentiation, and mechanical responses. Notably, this study characterizes early responses to exogenous ATP or UTP in a mammalian cell type using bulk RNA sequencing, providing valuable insights for future research.
Neuropeptide Y and peptide YY differentially modulate bitter- and fatty acid-evoked responses in human fungiform taste bud cells.
Iyer S, Gangakhedkar R, Bhuiyan I … +2 more , Montmayeur JP, Dotson CD
Am J Physiol Cell Physiol · 2026 Apr · PMID 41811172 · Publisher ↗
Numerous peptide hormones regulate feeding and metabolism via the brain and alimentary canal. Many of these peptides are also expressed, along with their cognate receptors, in the taste buds of the lingual epithelium. Am...
Numerous peptide hormones regulate feeding and metabolism via the brain and alimentary canal. Many of these peptides are also expressed, along with their cognate receptors, in the taste buds of the lingual epithelium. Among those present in the rodent oral cavity are peptides and receptors in the neuropeptide Y (NPY) family. Previous studies suggest that manipulation of NPY family peptide signaling can impact upon taste-related behavior, but it remains unclear whether these are mediated by changes in taste information processed by taste bud cells (TBCs), the primary sensory organs of the gustatory system, and whether human taste buds are similarly impacted by NPY family peptide signaling. In this report, we identify a complex modulatory role for NPY family peptides in shaping the tastant-evoked responses of human TBCs. Using a human fungiform taste bud cell line, we show that NPY and peptide YY (PYY), along with NPY receptor subtypes 1 and 2 (NPY1R and NPY2R), are expressed in TBCs. Importantly, NPY and PYY modulated the functional responses (assessed by calcium imaging and measurements of neurotransmitter release) of TBCs to bitter and fatty acid stimuli. The nature of modulation (i.e., enhancement or diminishment) was dependent not only on the peptide but also on the taste modality in question. Application of NPY1R and NPY2R antagonists indicated that the differential impacts of these peptides on TBC response parameters were mediated by differential NPY receptor activation. These data suggest that NPY family peptides directly and intricately modify gustatory sensory input by shaping TBC signaling. The conventional view of feeding regulation by metabolic peptides largely comprises "top-down" peptidergic signaling via the hypothalamus incorporating pre- and postprandial information via the gut-brain axis. Here, we suggest a role for these peptides adjusting "bottom-up" taste information streams that impact food choice and intake. This novel dimension of peptidergic modulation may provide a more comprehensive understanding of taste, feeding, and metabolism that better informs diagnostic and therapeutic developments related to feeding and metabolic regulation.
Vagal GABAergic signaling in autonomic control of cardiometabolic function.
Boychuk CR, Wang YB
Am J Physiol Cell Physiol · 2026 Apr · PMID 41811137 · Full text
Gamma-aminobutyric acid (GABA) and its receptors play a critical role in maintaining the balance between excitatory and inhibitory neurotransmission in the central nervous system, including autonomic regulatory regions t...
Gamma-aminobutyric acid (GABA) and its receptors play a critical role in maintaining the balance between excitatory and inhibitory neurotransmission in the central nervous system, including autonomic regulatory regions that control cardiometabolic function. Vagal circuits facilitate bidirectional communication between peripheral organs and the brain to elicit autonomic reflexes and modulate complex adaptive behavior to preserve cardiometabolic homeostasis. Dampened vagal activity can lead to the development of cardiometabolic diseases. Emerging evidence over the past decade identifies inhibitory GABAergic signaling in key vagal regulatory regions as a potential mechanism underlying vagal dysfunction linked to cardiometabolic disease. In this review, we discuss recent studies exploring GABAergic signaling modulation in vagal circuits, focusing on the regulation of food intake, cardiac function, and glucose metabolism-critical physiological processes that are often disrupted in cardiometabolic disease. We outline GABAergic signaling properties within key vagal reflex circuits, namely, vagal sensory afferents, nucleus tractus solitarius, and vagal motor neurons, and discuss how cardiometabolic stressors, as well as disease states, remodel vagal GABAergic signaling.
Muscle collagen accumulation is not a universal feature of human aging: a systematic review.
Schweitzer AM, Abercrombie MJ, Losciale JM … +1 more , Mitchell CJ
Am J Physiol Cell Physiol · 2026 May · PMID 41811105 · Publisher ↗
The extracellular matrix is critical to skeletal muscle structure and function, with collagen its largest component. Fibrosis, excessive collagen accumulation, disrupts muscle function. Although animal studies consistent...
The extracellular matrix is critical to skeletal muscle structure and function, with collagen its largest component. Fibrosis, excessive collagen accumulation, disrupts muscle function. Although animal studies consistently report age-related intramuscular collagen accumulation, human findings are inconsistent. This systematic review evaluated primary, peer-reviewed studies to assess if collagen accumulation is a universal feature of human aging. The review was registered on PROSPERO (CRD42024569964). Following PRISMA guidelines, five databases [MEDLINE (Ovid), Web of Science, Scopus, CINAHL, and SPORTDiscus] were searched in January 2026 for studies comparing intramuscular collagen/extracellular matrix content in healthy young and older (>60 yr) adults. Eligible studies used histological or hydroxyproline techniques to quantify collagen/extracellular matrix content. Study screening, review, data extraction, and risk of bias were performed independently by two reviewers. Results were synthesized narratively. Nine studies (including 122 young and 119 older adults) were included. Four reported no age-related differences, four showed age-related intramuscular collagen/extracellular matrix accumulation, and one found equivocal results when distinguishing perimysial from endomysial collagen. Considerable heterogeneity was observed in collagen quantification methods and control of mediators, including hypertension, diabetes, aerobic fitness, and physical activity. Studies with rigorous control generally found no age-related differences, whereas those with limited control generally reported age-related collagen accumulation. Collagen accumulation is not an inevitable feature of human chronological aging. Observed differences may instead reflect comorbidities or lifestyle factors associated with aging; thus, through these mediators, muscle collagen accumulation may be elevated in older populations. Future studies should control mediators and investigate mechanisms regulating collagen in skeletal muscle.
How temperature tunes muscle mechanics during eccentric contractions.
Askew GN, Kissane RWP
Am J Physiol Cell Physiol · 2026 Apr · PMID 41801770 · Full text
Eccentric muscle contractions occur when muscles actively lengthen, acting as brakes that dissipate energy and stabilize joints. When actively stretched, muscle force rises in two phases: an initial steep increase (phase...
Eccentric muscle contractions occur when muscles actively lengthen, acting as brakes that dissipate energy and stabilize joints. When actively stretched, muscle force rises in two phases: an initial steep increase (phase-1), followed by a slower, sustained rise (phase-2). The temperature sensitivity of this response is poorly understood, despite its relevance for musculoskeletal models that often rely on data collected at nonphysiological temperatures. We studied active lengthening contractions in the mouse extensor digitorum longus muscle at 17°C, 27°C, and 37°C. Force development in both phases was temperature-sensitive. Phase-1 stiffness decreased at higher temperatures, consistent with faster ATP-dependent cross-bridge detachment, and contributions from mechanical strain-dependent detachment. In phase-2, stiffness increased with temperature, consistent with stronger and faster titin-actin interactions. The transition between phases (muscle "give") varied with temperature and may reflect lower temperatures delaying cross-bridge detachment and engagement of the parallel elastic elements. Together, these findings highlight the intrinsic tuning of muscle mechanics, with potential implications for susceptibility to muscle damage under different thermal conditions, and provide a foundation for the development for more accurate musculoskeletal models. Muscles sometimes work as brakes, generating force while they lengthen. We show this force rises in two phases, both strongly affected by temperature, reflecting distinct underlying mechanisms. Phase-1 stiffness decreases at higher temperatures, consistent with faster cross-bridge detachment. In contrast, phase-2 stiffness increases with temperature, implying enhanced and more rapid titin-actin binding. These temperature-dependent changes reveal how muscles are tuned to resist active stretch, with potential implications for susceptibility to damage under varying thermal conditions.
Exploring the diverse roles of ketones in cellular physiology.
Falkenhain K, Little JP, Hawke TJ
Am J Physiol Cell Physiol · 2026 May · PMID 41801680 · Publisher ↗
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Bugs as drugs: parasite biomolecules as novel therapeutics against breast cancer.
Gonzalez SB, Shivam P, Ball D … +8 more , Ajisegiri SB, Osi I, Misra S, Mutchler AL, Lindsey ML, Martin PM, Sakwe AM, Nde PN
Am J Physiol Cell Physiol · 2026 Apr · PMID 41784099 · Publisher ↗
Contemporary breast cancer treatments include chemotherapy, surgery, and radiation therapy, all of which are invasive or accompanied by severe side effects. Although emerging research suggests that parasites have unique...
Contemporary breast cancer treatments include chemotherapy, surgery, and radiation therapy, all of which are invasive or accompanied by severe side effects. Although emerging research suggests that parasites have unique features that may be capitalized to develop innovative cancer treatments, the idea of using parasites for therapeutic purposes has been around for more than 3,500 yr. Parasites constitute a novel source of biomolecules with potent immunomodulatory and antitumor properties. This review summarizes our current knowledge on how components of the host response to parasite infection, specifically the inflammatory response, could be exploited to develop novel therapeutics for breast cancer. By identifying the molecular mechanisms behind parasite-induced antitumor properties, pathogen biomolecules could be potentially used as effective therapeutic alternatives or additives against breast cancer.
M2 muscarinic receptor-dependent contractions of airway smooth muscle are mediated by inhibition of Kv7 channels.
Ghosh S, Rabab KE, Hollywood MA … +2 more , Thornbury KD, Sergeant GP
Am J Physiol Cell Physiol · 2026 Apr · PMID 41784087 · Publisher ↗
Cholinergic tone is elevated in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthma. Acetylcholine contracts the airways by binding to M2 and M3 muscarinic receptors on airway smooth musc...
Cholinergic tone is elevated in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthma. Acetylcholine contracts the airways by binding to M2 and M3 muscarinic receptors on airway smooth muscle cells. The purpose of the present study was to investigate whether M2R-dependent contractions of airway smooth muscle (ASM) involved inhibition of Kv7 channels. Real-time quantitative PCR (qPCR) and immunocytochemistry revealed that Kv7.5 was the highest expressed Kv7 subtype in mouse ASM, followed by Kv7.4. Cholinergic nerve-evoked contractions of mouse bronchial rings were induced by electrical field stimulation (EFS). Reducing the stimulus interval from 100 to 10 s augments EFS-evoked contractions via an M2R-dependent pathway. Inhibition of Kv7 channels with XE991 increased the amplitude of EFS responses at 100-s intervals, but not at 10 s. The Kv7 channel openers ICA069673 and ML213 inhibited M2R-dependent responses and similar effects were obtained using the adenylate cyclase activator forskolin and the PKA activator 6MB-cAMP. The effects of M2R activation on Kv7 currents were determined by examining the effect of carbachol on HEK293 cells co-expressing M2Rs with Kv7.4 or Kv7.5. Activation of M2Rs reduced the amplitude of both Kv7.4 and Kv7.5 currents. ICA069673 reversed the inhibitory effects of M2R activation on Kv7.4, whereas ML213 reversed the effects on both Kv7.4 and Kv7.5. Inclusion of PIPdiC8 in the pipette prevented the inhibitory effects of carbachol on Kv7.4, but not Kv7.5, whereas 6MB-cAMP potentiated Kv7.5 currents but not Kv7.4. These data suggest that M2Rs exert their contractile effects on ASM by inhibiting Kv7 channels via pathways that deplete PIP and reduce PKA activity. Cholinergic tone is elevated in airway smooth muscle (ASM) of patients with COPD and asthma. Here, we report that M2R-dependent contractions of ASM were inhibited by activators of Kv7.4 and Kv7.5 channels. The cholinergic agonist, carbachol (CCh), suppressed Kv7 currents recorded from HEK293 cells co-expressing M2Rs and Kv7.4 or Kv7.5. These data suggest that the bronchoconstrictor effects of ACh involve M2R-mediated inhibition of Kv7.4 and Kv7.5 channels.
New insights into immunoporosis: the impact of ovariectomy on immune cell population in lymph nodes and spleen.
Sommer NG, Jandl K, Okutan B … +4 more , Schwarze UY, Freudenthal-Siefkes JE, Herber V, Weinberg AM
Am J Physiol Cell Physiol · 2026 Apr · PMID 41779033 · Publisher ↗
It is increasingly appreciated that the immune cells and inflammatory mediators contribute to the impaired osteogenic potential under osteoporotic conditions. Previous studies in experimental animals focused on immune ce...
It is increasingly appreciated that the immune cells and inflammatory mediators contribute to the impaired osteogenic potential under osteoporotic conditions. Previous studies in experimental animals focused on immune cells isolated from blood or bone marrow. Here we highlight the importance of unraveling the interactions between peripheral tissues, such as spleen and lymph nodes, and bone morphologic markers. Ovariectomized (OVX) animals underwent bilateral ovariectomy at the age of 9 mo. Four, 8, and 12 wk after ovariectomy, osteoporotic parameters and the immunoprofile were investigated by flow cytometric analysis of blood, lymph node, and spleen paired with immunohistochemistry. Ex vivo high-resolution micro-computed tomography (micro-CT) and hard tissue histology were performed on the excised tibiae. We observed trabecular bone loss, with corresponding decreases in bone volume to tissue volume (BV/TV), trabecular number (Tb.N), and connectivity density (Conn.D), as well as an increase in trabecular separation (Tb.Sp) in the OVX rats after 12 wk. Quantitative FACS analysis revealed significantly decreased percentage of granulocytes in lymph nodes at 12 wk in OVX. Correlation of distinct immune cell populations to bone morphologic markers showed that the percentage of granulocytes positively correlated with the Tb.N and Conn.Dn and negatively with the Tb.Sp both in the lymph nodes and in the spleen at 8 wk. At 12 wk after ovariectomy, however, the percentage of granulocytes correlated negatively with BV/TV, Tb.Th, and Tb. N. There was no correlation between distinct immune cells in the blood and bone morphologic markers. Hence, the presented data highlight the unmet need to investigate other compartments rather than blood and bone marrow. There is supporting immunological evidence in the development of osteoporosis highlighted by bone alterations. Measurements of immune cells in the blood and bone marrow do not always reflect the multifactorial, pathologic situation linked to osteoporosis. Here, we pinpoint to distinct immune cell populations in peripheral tissues, especially in lymph nodes, which are affected during the onset of osteoporosis.
Macrophages, muscle stem cells, and repair; immunohistochemical characteristics in muscle growth impairments in children with cerebral palsy.
Meza G, Kahn RE, Patel NM … +3 more , Larson JE, Swaroop VT, Dayanidhi S
Am J Physiol Cell Physiol · 2026 Apr · PMID 41778682 · Full text
Children with cerebral palsy (CP) have muscle growth impairments (muscle contractures), altered walking patterns and show markers of inflammation. During muscle repair, macrophages coordinate with muscle stem cells-satel...
Children with cerebral palsy (CP) have muscle growth impairments (muscle contractures), altered walking patterns and show markers of inflammation. During muscle repair, macrophages coordinate with muscle stem cells-satellite cells (MuSCs), which have previously been shown to be altered in abundance and function in children with CP. We investigated whether ) macrophage populations in contractured muscles of children with CP are similar to typically developing (TD) children with a chronic anterior cruciate ligament (ACL)-tear and ) macrophages, capillaries, MuSC, myonuclei, centrally nucleated fibers were associated with each other, indicative of repair. Thirty-six subjects participated in this study (CP: 11.2 ± 0.7 yr, 18 M/12F, TD: 13.5 ± 0.8 yr, 3 M/3 F). Muscle biopsies were obtained during surgical correction for muscle contractures-adductors/gastrocnemius (CPCon), or vastus lateralis (TD-ACL and CP NonCon). Muscle cross sections were immunohistochemically labeled for total, anti-inflammatory (M2) macrophages, capillaries, myofiber boundaries, whereas MuSC abundance, activation, and proliferation information were used from a prior study. Macrophage subpopulations in CPCon were similar to TD-ACL muscles. Within CPCon, there were positive associations between total, M1 macrophages, and MuSC content ( = 0.54, = 0.70, < 0.05, respectively), but not in the CP NonCon muscles. Centrally nucleated fibers, myonuclear abundance, and MuSC content were also positively associated with each other only in the CPCon muscles ( = 0.65, = 0.46, = 0.66, < 0.05, respectively). In TD-ACL injured muscles, similar associations were seen between macrophages and MuSC, central nucleation and myonuclear abundance. Collectively, our data suggest that contractured muscles in children with CP may be in a state of repair, similar to ACL-injured TD children. Muscle growth impairments seen as muscle contractures are common in children with cerebral palsy. Here we show these muscles appear to have altered macrophage populations, which are similar to joint injury-induced muscle inflammation in typically developing children. Only within contractured muscles, macrophage content, muscle stem cell abundance, capillary density and fiber characteristics are positively associated with each other, indicative of repair, similar to that seen in joint injury-induced muscle inflammation.
Mitochondria in muscle stem cell biology: gatekeepers of fate, function, and regeneration.
Khacho M, Burelle Y
Am J Physiol Cell Physiol · 2026 Apr · PMID 41778679 · Publisher ↗
Muscle stem cells (MuSCs) are essential for skeletal muscle regeneration and maintenance of tissue homeostasis. However, their regenerative capacity declines with aging and in several pathological conditions, including n...
Muscle stem cells (MuSCs) are essential for skeletal muscle regeneration and maintenance of tissue homeostasis. However, their regenerative capacity declines with aging and in several pathological conditions, including neuromuscular diseases, cancer cachexia, sepsis, and metabolic disorders. Increasing evidence has identified mitochondria as key regulators of MuSC behavior, influencing quiescence, activation, self-renewal, and differentiation during myogenesis. In addition to their role in energy production, mitochondria function as metabolic and signaling hubs that integrate cellular and environmental cues to control stem cell fate decisions. This review summarizes current knowledge on the role of mitochondria in MuSC biology, including the contribution of mitochondrial bioenergetics and metabolic signaling to MuSC state transitions, the importance of mitochondrial network dynamics in regulating stem cell function, and the role of mitochondrial quality control mechanisms such as mitophagy and selective mitochondrial inheritance. We further discuss how mitochondrial dysfunction contributes to impaired MuSC function in aging and muscle-wasting conditions and highlight potential therapeutic strategies targeting mitochondrial pathways to improve muscle regeneration.
Bioactive peptide matrikines: discovery approaches for skin rejuvenation.
Birtles T, El-Houni Z, Mistry K … +6 more , Ozols M, Bradley EJ, Bell M, Swift J, Sherratt MJ, Eckersley A
Am J Physiol Cell Physiol · 2026 Apr · PMID 41770626 · Publisher ↗
Aging of human skin is driven in part by cumulative damage to extracellular matrix (ECM) proteins, resulting in wrinkles, laxity, and reduced capacity to heal. Bioactive peptide matrikines are promising therapeutic agent...
Aging of human skin is driven in part by cumulative damage to extracellular matrix (ECM) proteins, resulting in wrinkles, laxity, and reduced capacity to heal. Bioactive peptide matrikines are promising therapeutic agents capable of stimulating ECM regeneration and remodeling. This review focuses on how the discovery strategies to identify these peptides have evolved over several decades of cosmeceutical use. Early peptide matrikines were identified primarily through repetitive in vitro testing, based on prior knowledge of a protein or functional region. More recently, there is a focus on in silico prediction of bioactive peptide sequences, implementing techniques such as protease cleavage prediction, protein sequence motif screening, molecular docking, and machine learning algorithms to rapidly derive peptide candidates in silico. We highlight our recently developed in silico to in vivo discovery pipeline, which integrates prediction of aging-related cleavage susceptibility of ECM proteins with comprehensive in vitro and in vivo testing, culminating in the identification of two tetrapeptides (pal-GPKG and pal-LSVD) which act synergistically to enhance ECM regeneration in aged skin. Looking forward, advances in deep learning cleavage prediction models, molecular modeling, and in vitro testing with three-dimensional (3-D) skin models will accelerate the discovery and translation of novel matrikines for skin regeneration and broader biomedical applications, such as wound repair.
Interstitial cells and arrhythmia.
Rog-Zielinska EA, Grune J, Kessler T … +2 more , Lother A, Kohl P
Am J Physiol Cell Physiol · 2026 Apr · PMID 41770413 · Full text
The electrophysiological relevance of interstitial nonmyocytes for cardiac electrophysiology arises from their abundant direct and indirect interactions with cardiac myocytes. This review defines the interstitium, explor...
The electrophysiological relevance of interstitial nonmyocytes for cardiac electrophysiology arises from their abundant direct and indirect interactions with cardiac myocytes. This review defines the interstitium, explores biophysical and biochemical mechanisms of interactions between interstitial components and cardiac myocytes, illustrates consequences of these interactions for heart rhythm, and identifies targets for further research in this area.
Interleukin-1β downregulates K currents through K1.6 channels and promotes apoptosis by enhancing Ca influx in chondrocytes.
Kurata T, Suzuki Y, Tateno S … +7 more , Miyaki S, Kondo R, Bernotiene E, Mobasheri A, Giles WR, Imaizumi Y, Yamamura H
Am J Physiol Cell Physiol · 2026 Apr · PMID 41770339 · Publisher ↗
Chronic inflammation of the knee joint can induce chondrocyte death, leading to osteoarthritis (OA). Ca influx through Ca channels expressed in the chondrocyte plays a key role in promoting the inflammation and chondrocy...
Chronic inflammation of the knee joint can induce chondrocyte death, leading to osteoarthritis (OA). Ca influx through Ca channels expressed in the chondrocyte plays a key role in promoting the inflammation and chondrocyte death. Voltage-gated K (K) channels can modulate this Ca influx by regulating the resting membrane potential (RMP) in chondrocytes. Although it has been reported that an increase in intracellular Ca concentration ([Ca]) is associated with OA progression, the molecular mechanism(s) remain unclear. Therefore, the main goal of this study was to identify the mechanisms responsible for increases in [Ca] in chondrocytes as a basis for understanding its role in OA progression. Our results reveal that in mouse chondrocytes treated with IL-1β the expression of K1.6 channels was downregulated, and this resulted in a significant depolarization of the RMP. This downregulation of K1.6 channels in chondrocytes was also detected in OA model mice and in patients diagnosed with progressive OA. Furthermore, IL-1β treatment increased the expression of voltage-gated Ca1.2 channels. IL-1β-treated chondrocytes consistently showed an increase in resting [Ca], reduction or loss of mitochondrial membrane potential, and facilitation of apoptosis. These pathological changes were suppressed by recovery of K1.6 channel expression or by treatment with nifedipine, a Ca1.2 channel inhibitor. In conclusion, IL-1β-induced downregulation of K1.6 channels leads to ) depolarization of the RMP, ) an enhancement of Ca influx through Ca1.2 channels, and ) an increase in [Ca], which induces mitochondrial dysfunction and apoptosis in chondrocytes. Accordingly, K1.6 and Ca1.2 channels may be therapeutic targets for OA. Our results reveal that K1.6 channels in mouse chondrocytes contribute to cell survival by regulating the resting membrane potential (RMP) and thus modulating intracellular Ca concentration ([Ca]). Specifically, IL-1β can downregulate K1.6 channels and result in RMP depolarization, which increases Ca influx through Ca1.2 channels and promotes mitochondrial dysfunction and apoptosis. Downregulation of K1.6 channels was detected in chondrocytes of osteoarthritis (OA) model mice and OA patients. These findings suggest that K1.6 and/or Ca1.2 channels may be potential therapeutic targets for OA.
Time of day of skeletal muscle injury is a factor in short- and long-term regeneration outcomes.
Scurto DL, Ouellette JM, Kirincic TA … +5 more , Crain NG, Marangelli VW, Mozafari A, Milne KJ, Krause MP
Am J Physiol Cell Physiol · 2026 Apr · PMID 41770308 · Publisher ↗
Skeletal muscle regeneration is a dynamic process diurnally regulated by circadian rhythms, which govern key myogenic factors. Previous studies have shown that the timing of muscle injury influences early regeneration ou...
Skeletal muscle regeneration is a dynamic process diurnally regulated by circadian rhythms, which govern key myogenic factors. Previous studies have shown that the timing of muscle injury influences early regeneration outcomes, but it remains unclear whether these effects persist beyond early acute regeneration events. This study investigated whether the time of day at which muscle injury occurs alters postregeneration outcomes in mice. C57BL/6NCrl mice ( = 80) received bilateral cardiotoxin (CTX) injury to the tibialis anterior (TA) during either the rest phase (ZT2-ZT4) or active phase (ZT14-ZT16), with tissues collected at 7- or 42- days postinjury (DPI). All mice were matched with uninjured controls. Gross functional performance, assessed via rotarod and grip strength testing, demonstrated no differences between rest and active phase injury groups across repeated testing. A series of immunohistological analyses was performed to assess general fiber morphology and markers of regenerative state. Although the injury phase had largely no effect on most parameters, myofiber size distributions consistently displayed more small fibers in rest phase-injured mice, regardless of sex. Although there were notable differences in myosin isoform expression, such trends were observed at both 7 and 42 DPI, suggesting a specific morphological effect of injury timing. These findings indicate that the circadian phase at which skeletal muscle injury occurs causes a persistent influence on the size distribution of regenerating myofibers, independent of functional recovery, and highlights the need to consider time-of-day and the contribution of postinjury activity as a biological variable in muscle regeneration research. The timing of skeletal muscle injury influences myofiber morphology postregeneration. Although functional capacity was unaffected by injury timing, muscles injured in the circadian rest phase exhibited a greater quantity of smaller myofibers compared with their active phase counterparts. This was not accompanied by differences in regenerating cell morphology or nuclear centralization. This research suggests that circadian timing of injury exerts a lasting effect on muscle regeneration, and may reflect time-of-day-specific regulation of muscle remodeling.
A novel cell indirect calorimetry method unveils the metabolic fluxomic signatures of human monocyte-derived M(LPS + IFN-γ) and M(IL-4) macrophages.
Cinquegrani G, Spigoni V, Fantuzzi F … +6 more , D'Antuono A, Bagnaresi F, Giordano E, Burato A, Dei Cas A, Bonadonna RC
Am J Physiol Cell Physiol · 2026 Apr · PMID 41770302 · Publisher ↗
Macrophages (MΦ) display distinct immunometabolic phenotypes upon polarization. While transcriptomic analyses have suggested divergent metabolic programs in human M(LPS + IFN-γ) and M(IL-4) MΦ, a comprehensive assessment...
Macrophages (MΦ) display distinct immunometabolic phenotypes upon polarization. While transcriptomic analyses have suggested divergent metabolic programs in human M(LPS + IFN-γ) and M(IL-4) MΦ, a comprehensive assessment of their metabolic fluxes is lacking. The aim of this study is to ) develop and validate a novel indirect microcalorimetry method for quantifying cellular metabolic fluxes, and ) exploit it to characterize fluxomic signatures of polarized human monocyte-derived macrophages. MΦ from healthy donors were differentiated into unstimulated macrophages (M0), M(LPS + IFN-γ), and M(IL-4) phenotypes and studied in four defined media: substrate-free, glucose, glycyl-glutamine, and glucose + glycyl-glutamine. A steady-state fluxomic model was constructed by integrating four independent measures, oxygen consumption and proton production (Seahorse XFp) and lactate and ammonia release (microfluorimetry), into stoichiometric equations of metabolism (SAAM II software). Fluxes revealed that macrophages rely on glucose to sustain glycolysis, contributing ∼30% of citrate synthase flux, and predominantly on lipids for net citrate synthesis (first step of TCA cycle). Upon polarization, M(LPS + IFN-γ) macrophages showed increased anaerobic glycolysis versus M0 and M(IL-4), with similar TCA fluxes to M0. In contrast, M(IL-4) macrophages exhibited higher TCA and malic enzyme fluxes, especially with glucose and glycyl-glutamine, and a trend toward enhanced lipid oxidation. This novel method enables precise quantification of bioenergetic fluxes. In human MΦ, it reveals that M(LPS + IFN-γ) and M(IL-4) subsets exhibit distinct metabolic phenotypes, consistent with their immunological roles. These results resolve transcriptomic-metabolic discrepancies and provide a robust framework for assessing immunometabolism in primary human cells. We present a novel microcalorimetry-based approach for quantifying metabolic fluxes in human cells. Applied to primary monocyte-derived human macrophages, this method reveals that M(LPS + IFN-γ) and M(IL-4) subsets exhibit distinct fluxomic profiles: the former favors glycolysis, whereas the latter shows enhanced TCA cycle activity and lipid oxidation. These findings resolve previous discrepancies between transcriptomic and functional data and provide a robust framework for investigating immunometabolism in primary human cells.
Dynamic insights into cellular mechanics and membrane undulations in vascular smooth muscle cells.
Khatiwada N, Sanyour HJ, Hammam IA … +8 more , Li Z, McLean J, Dwamena A, Perez A, See GE, Wang H, Liu M, Hong Z
Am J Physiol Cell Physiol · 2026 Apr · PMID 41758219 · Full text
Dynamic oscillations in cell mechanics are fundamental yet poorly understood features of living cells. In vascular smooth muscle cells (VSMCs), such oscillations may play important roles in regulating contractility, mech...
Dynamic oscillations in cell mechanics are fundamental yet poorly understood features of living cells. In vascular smooth muscle cells (VSMCs), such oscillations may play important roles in regulating contractility, mechanosensitivity, and vascular function. Here, real-time atomic force microscopy (AFM), advanced signal processing, biochemical analysis, and machine learning-based image quantification were combined to investigate the spatiotemporal coupling between cellular mechanics, membrane undulation, cytoskeletal organization, and actomyosin signaling in VSMCs. Continuous AFM force and height mapping revealed intrinsic, low-frequency oscillations in both elastic modulus and membrane roughness, with dominant modes at ∼0.55, ∼1.6, and ∼3.5 mHz, that were absent in passive material controls. Pharmacological modulation of the actin cytoskeleton demonstrated frequency-dependent regulation of these oscillations: stabilization of F-actin with jasplakinolide increased cellular stiffness and selectively enhanced low-frequency mechanical oscillations while suppressing membrane roughness fluctuations, whereas actin depolymerization with latrunculin A reduced stiffness and mechanical oscillations but markedly amplified membrane undulations. Confocal imaging and deep learning-based analysis confirmed corresponding changes in actin fiber density and organization. Moreover, inhibition of myosin light chain kinase (MLCK) signaling reduced cell stiffness and preferentially attenuated higher-frequency oscillatory modes, whereas biochemical analysis revealed differential regulation of MLCK phosphorylation following actin perturbation. Together, our findings suggest that changes in actin organization and MLCK-driven contractility control different patterns of mechanical oscillation and membrane behavior in VSMCs. This helps us better understand how smooth muscle mechanics are regulated across different scales and why disruptions in these processes could influence vascular function and disease. In this study, we observed previously unrecognized mechanical oscillations in vascular smooth muscle cells that occur at specific frequencies and remain synchronized across the cell, alongside coordinated membrane movements. By combining real-time atomic force microscopy with targeted perturbations of the cytoskeleton and myosin light chain kinase activity, we found that different oscillatory behaviors depend on actin organization and contractile signaling. These results outline a multiscale framework for understanding how smooth muscle mechanics are dynamically controlled.
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