Acidosis

During high-intensity exercise a lactic-acidosis occurs with raised myoplasmic and plasma concentrations of lactate- and protons ([lactate-], [H+] or pH). We critically evaluate whether this causes/contributes to fatigue during human exercise. Increases of [lactate-] per se (to 25 mM in plasma, 50 mM intracellularly) exert little detrimental effect on muscle performance while ingestion/infusion of lactate- can be ergogenic. An exercise-induced intracellular acidosis at the whole-muscle level (pHi falls from 7.1-7.0 to 6.9-6.3), incorporates small changes in slow-twitch fibres (pHi ~ 6.9) and large changes in fast-twitch fibres (pHi ~ 6.2). The relationship between peak force/power and acidosis during fatiguing contractions varies across exercise regimes implying that acidosis is not the sole cause of fatigue. Concomitant changes of other putative fatigue factors include phosphate metabolites, glycogen, ions and reactive oxygen species. Acidosis to pHi 6.7-6.6 at physiological temperatures (during recovery from exercise or induced in non-fatigued muscle), has minimal effect on force/power. Acidosis to pHi ~ 6.5-6.2 per se reduces maximum force (~12%), slows shortening velocity (~5%), and lowers peak power (~22%) in non-fatigued muscles/individuals. A pre-exercise induced-acidosis with ammonium chloride impairs exercise performance in humans and accelerates the decline of force/power (15-40% initial) in animal muscles stimulated repeatedly in situ. Raised [H+]i and diprotonated inorganic phosphate ([H2PO4-]i) act on myofilament proteins to reduce maximum cross-bridge activity, Ca2+-sensitivity, and myosin ATPase activity. Acidosis/[lactate-]o attenuates detrimental effects of large K+-disturbances on action potentials and force in non-fatigued muscle. We propose that depressive effects of acidosis and [H2PO4-]i on myofilament function dominate over the protective effects of acidosis/lactate- on action potentials during fatigue. Raised extracellular [H+]/[lactate-] do not usually cause central fatigue but do contribute to elevated perceived exertion and fatigue sensations by activating group III/IV muscle afferents. Modulation of H+/lactate- regulation (via extracellular H+-buffers, monocarboxylate transporters, carbonic anhydrase, carnosine) supports a role for intracellular acidosis in fatigue. In conclusion, current evidence advocates that severe acidosis in fast-twitch fibres can contribute to force/power fatigue during intense human exercise.

The ketogenic diet (KD) induces prolonged hyperketonemia, characterized by elevated circulating level of β-hydroxybutyrate. However, the KD can negatively affect host metabolic health by altering the gut microbial community. Despite this, the regulatory effect of the gut microbiota on hepatic ketogenesis and triacylglycerol (TAG) accumulation during a KD remains poorly understood. Here, we hypothesized that the commensal bacterium regulates hepatic lipid metabolism in association with KD-induced hyperketonemia. The KD disrupts the remodeling of the gut microbiota following antibiotic-induced depletion. The capacity for ketogenesis and the severity of TAG accumulation in the liver closely correlated with changes in the gut microbial composition and the up-regulation of hepatic farnesoid X receptor (FXR), peroxisome proliferator-activated receptor alpha (PPARα), and diacylglycerol O-acyltransferase 2 (DGAT2), which were modulated by bile acid metabolism through the gut-liver axis. The commensal bacterium Clostridium perfringens type A is particularly implicated in prolonged hyperketonemia, exacerbating hepatic ketogenesis and steatosis by disrupting secondary bile acid metabolism. The increased conversion of deoxycholic acid to 12-ketolithocholic acid represents a critical microbial pathway during C. perfringens colonization. These findings illuminate the adverse effects of the gut microbiota on hepatic adaptation to a KD and highlight the regulatory role of C. perfringens in ketonic states.

Osteoarthritis (OA) lacks disease-modifying therapies, in part because key features of the joint microenvironment remain underappreciated. One such feature is localized acidosis, characterized by sustained reductions in extracellular pH within the cartilage, meniscus, and the osteochondral interface despite near-neutral bulk synovial fluid. We synthesize current evidence on the origins, sensing, and consequences of joint acidosis in OA. Metabolic drivers include hypoxia-biased glycolysis in avascular cartilage, cytokine-driven reprogramming in the synovium, and limits in proton/lactate extrusion (e.g., monocarboxylate transporters (MCTs)), with additional contributions from fixed-charge matrix chemistry and osteoclast-mediated acidification at the osteochondral junction. Acidic niches shift proteolysis toward cathepsins, suppress anabolic control, and trigger chondrocyte stress responses (calcium overload, autophagy, senescence, apoptosis). In the nociceptive axis, protons engage ASIC3 and sensitize TRPV1, linking acidity to pain. Joint cells detect pH through two complementary sensor classes: proton-sensing GPCRs (GPR4, GPR65/TDAG8, GPR68/OGR1, GPR132/G2A), which couple to Gs, Gq/11, and G12/13 pathways converging on MAPK, NF-κB, CREB, and RhoA/ROCK; and proton-gated ion channels (ASIC1a/3, TRPV1), which convert acidity into electrical and Ca2+ signals. Therapeutic implications include inhibition of acid-enabled proteases (e.g., cathepsin K), pharmacologic modulation of pH-sensing receptors (with emerging interest in GPR68 and GPR4), ASIC/TRPV1-targeted analgesia, metabolic control of lactate generation, and pH-responsive intra-articular delivery systems. We outline research priorities for pH-aware clinical phenotyping and imaging, cell-type-resolved signaling maps, and targeted interventions in 'acidotic OA' endotypes. Framing acidosis as an actionable component of OA pathogenesis provides a coherent basis for mechanism-anchored, locality-specific disease modification.

Aggressive tumours are defined by microenvironmental stress adaptation and metabolic reprogramming. Within this niche, lipid droplet accumulation has emerged as a key strategy to buffer toxic lipids and suppress ferroptosis. Lipid droplet formation can occur via de novo lipogenesis or extracellular lipid-scavenging. However, how tumour cells coordinate these processes remains poorly understood. Here we identify a chondroitin sulfate (CS)-enriched glycocalyx as a hallmark of the acidic microenvironment in glioblastoma and central nervous system metastases. This CS-rich glycocalyx encapsulates tumour cells, limits lipid particle uptake and protects against lipid-induced ferroptosis. Mechanistically, we demonstrate that converging hypoxia-inducible factor and transforming growth factor beta signalling induces a glycan switch on syndecan-1-replacing heparan sulfate with CS-thereby impairing its lipid-scavenging function. Dual inhibition of CS biosynthesis and diacylglycerol O-acyltransferase-1, a critical enzyme in lipid droplet formation, triggers catastrophic lipid peroxidation and ferroptotic cell death. These findings define glycan remodelling as a core determinant of metabolic plasticity, positioning the dynamic glycocalyx as a master regulator of nutrient access, ferroptotic sensitivity and therapeutic vulnerability in cancer.