Biologists have spent decades mapping how cells police their proteins. Chaperones refold misfolded chains, the proteasome shreds irreparable ones, and autophagy devours bulky aggregates. DNA repair pathways similarly guard the genome. But glycogen, a polymer of glucose assembled by glycogen synthase and sculpted by branching enzyme, has lacked an obvious surveillance mechanism. That gap matters clinically. In adults, aberrant, poorly branched glycogen builds up as polyglucosan bodies in disorders such as adult polyglucosan body disease, a condition caused by mutations in the branching enzyme gene GBE1 that can produce progressive weakness, numbness and neurogenic bladder. Until now, no one had identified a cellular machine that actively detects and removes these defective polymers before they crystallize into disease.

The Cambridge team began with genetics. Mice engineered to lack the ligase activity of RNF213, an enormous E3 ubiquitin ligase previously implicated in Moyamoya disease, a rare cerebrovascular disorder, accumulated polyglucosan in specific brain regions: the cerebellum, the pons and the hippocampus. That pattern of accumulation pointed to a protective role in astrocytes, the star-shaped support cells that stockpile much of the brain’s glycogen. The inference was striking. If removing RNF213’s enzymatic activity caused polyglucosan to pile up, then RNF213’s normal job might be to recognize aberrant glycogen and mark it for destruction, much as E3 ligases mark damaged proteins.

To test that idea directly, the researchers built a cell-based system in which cells manufacture polyglucosan, the pathological, sparsely branched form of glycogen. In these cells, RNF213 selectively attached ubiquitin to the abnormal polymer while leaving healthy, well-branched glycogen untouched. That selectivity is the crux of the discovery. Quality control is only useful if it distinguishes good from bad, and here the enzyme appeared to do exactly that, reading the structural state of a carbohydrate granule and tagging only the defective version. The tagged polyglucosan was then engulfed by autophagosomes, the cell’s membrane-bound disposal vesicles, in a process the authors describe as autophagy of ubiquitylated aberrant glycogen.

How does a protein enzyme read the architecture of a sugar polymer? Cryo-electron microscopy provided the answer. Wanda Kukulski’s group at the University of Bern joined the effort to solve the structure of RNF213 bound to maltoheptaose, a linear seven-glucose fragment derived from glycogen. The images revealed that RNF213 carries a carbohydrate-binding module, CBM20, that grips linear oligosaccharides. This detail matters because normal glycogen is densely branched, studded with short side chains, whereas polyglucosan is comparatively linear and sparse. The CBM20 domain, the structure implies, acts as a molecular ruler that prefers the exposed linear stretches characteristic of aberrant glycogen.

The structural work also explained a paradox. When the researchers mutated the carbohydrate-binding surface of CBM20, RNF213 did not lose its activity; it gained it, promiscuously ubiquitylating even physiological glycogen. In other words, the binding domain normally restrains the enzyme, preventing it from attacking healthy glycogen and licensing activity only when the polymer presents the right structural cues. Disrupting that restraint converts a precise quality control factor into a blunt instrument. This regulatory logic, in which substrate recognition gates catalytic output, echoes themes from protein quality control but is here applied to a branched carbohydrate, a conceptual first.

Ubiquitylation is only the first step of disposal. The study traced what happens next through epistasis analysis, which places genes in a pathway by testing how mutations combine. RNF213 acts upstream of LUBAC, a linear ubiquitin chain assembly complex, suggesting a hierarchy in which one E3 ligase initiates tagging and a second elaborates the mark. The resulting ubiquitin coat on polyglucosan then recruits autophagy receptors, including SQSTM1, also known as p62, TAX1BP1 and optineurin. These adaptor proteins physically link the tagged cargo to the autophagy machinery, triggering uptake into autophagosomes and eventual degradation. The network implies that glycogen surveillance, like protein surveillance, is a multi-layered system with division of labor among several enzymes.

The discovery also reframes RNF213 itself. The gene has attracted intense clinical interest because loss-of-function variants cause Moyamoya disease, and the protein’s ligase activity has been linked to lipid droplet biology and innate immunity. Adding glycogen quality control to its portfolio suggests that RNF213 is a broad-spectrum surveyor of cytoplasmic polymers, and it raises the question of whether some Moyamoya pathology might involve glycogen mishandling in brain cells, a possibility the study does not directly establish but which now invites investigation. It also broadens the emerging concept of non-protein ubiquitylation, in which ubiquitin marks lipids and carbohydrates, into a central pillar of cellular housekeeping.

For medicine, the implications are tantalizing but early. Adult polyglucosan body disease and related glycogen storage disorders currently lack therapies that address the root problem of insoluble polymer accumulation. If the RNF213 pathway can be understood well enough to enhance, perhaps by stabilizing the enzyme’s activity or boosting the autophagy receptors it engages, cells might in principle be taught to clear polyglucosan before it accumulates. The mouse data showing region-specific polyglucosan buildup in the absence of RNF213 ligase activity provide a model for testing such strategies. Caution is warranted: the work identifies a mechanism, not a treatment, and translating ubiquitin biology into drugs has historically proven difficult.

Scientifically, the study’s deepest significance may be conceptual. Quality control, biologists now realize, is not a protein-only affair. DNA, RNA, lipids and now glycogen all fall under the ubiquitin system’s jurisdiction, each with dedicated sensors and disposal routes. The Cambridge and Bern teams have shown that even a humble energy store is inspected, tagged and recycled with the same molecular rigor applied to a misfolded enzyme. Cells, it turns out, do not merely fill their glycogen granules and forget them. They watch them, and when the branching goes wrong, they call in RNF213.

Subject of Research: Ubiquitin-dependent quality control of glycogen by the E3 ligase RNF213

Article Title: Quality control of glycogen through direct ubiquitylation by RNF213

Article References: Yip, M. C. J., Naydenova, K., Otten, E. G., Heatley, A., Moe, A., Anton, L., de los Reyes-Ramírez, L., Jolin, H. E., Langevin, F., Wiacek, M., Franco, C., Bertolotti, A., Kukulski, W., McKenzie, A. N. J., & Randow, F. (2026). Quality control of glycogen through direct ubiquitylation by RNF213. Nature. https://doi.org/10.1038/s41586-026-11139-6

Image Credits: AI Generated

DOI: 10.1038/s41586-026-11139-6

Keywords: glycogen, RNF213, ubiquitylation, autophagy, polyglucosan, E3 ligase, cryo-EM, CBM20, astrocytes, neurodegeneration, LUBAC, SQSTM1

The research team, led by Taira Kajisa and Toshiyuki Sakai of Toyo University, equipped 20 male athletes classified as Tier 3 Highly Trained/National with FreeStyle Libre 2 continuous glucose monitoring (CGM) sensors. These devices measure glucose in the interstitial fluid just beneath the skin, providing a reading every 15 minutes without needles during exercise. The cohort contributed 36 race-event datasets spanning track running, road relays, half-marathons, cross country, and race walking, generating 16,360 individual glucose data points collected from three days before to three days after each race.

The study design addressed a critical confound: carbohydrate intake. Athletes, all living in a team dormitory with standardized meals, completed solid carbohydrate consumption at least 120 minutes before race starts, and event regulations prohibited carbohydrate-containing fluids during races. This means the glucose elevations observed mid-race could not be explained by recent fueling. Fifteen of the athletes also wore sensors during high-intensity training sessions prescribed at the identical race pace, on matching course types, within eight days of the competition, enabling a rare within-subject comparison.

The statistical picture was unambiguous. Mean glucose during the pre-race hour climbed to 8.3 ± 1.5 millimolar, well above the cohort’s overall mean of 6.1 millimolar, and then surged to a competition peak of 11.2 ± 2.2 millimolar, nearly double typical resting values. After the finish line, glucose dropped sharply, falling to 6.7 millimolar within an hour. A repeated-measures analysis of variance confirmed a powerful effect of race phase, and paired comparisons adjusted with the Holm-Bonferroni procedure showed the jump from pre-race to during-race glucose carried a large effect size, with Cohen’s dz of 1.45.

The within-subject comparison between competition and training proved the study’s centerpiece. Peak interstitial glucose reached 12.91 ± 1.93 millimolar in races versus 11.02 ± 1.18 millimolar in matched training bouts, a mean difference of 1.89 millimolar with a 95 percent confidence interval of 1.06 to 2.72. The paired t-test yielded p = 0.000131, and the geometric mean ratio of 1.166 translates to approximately 17 percent higher competitive peaks. Exploratory analyses showed the difference was not driven by race distance: short events under 10 kilometers showed +2.17 millimolar, mid-distance events +2.15, and longer events +1.40, a gradient that actually runs opposite to what a pure intensity-difference explanation would predict.

What could drive this competition-specific hyperglycemia? The authors frame their findings within classical stress physiology. Competitive arousal activates the sympathetic nervous system, releasing epinephrine and norepinephrine, which stimulate the liver to break down glycogen and dump glucose into the bloodstream. Causal support exists in the literature: in adrenalectomized humans, adrenaline infusion during exercise directly increases hepatic glucose production. Crucially, muscle glycogen stores, though five times larger than the liver’s roughly 100 grams, cannot release glucose into blood, so the racing hyperglycemia must reflect hepatic mobilization, not muscle fuel leaking into circulation.

A preliminary validation experiment underscored the technique’s reliability. A sub-elite marathoner (personal best under three hours) ran 5 kilometers fasted at 4 minutes per kilometer while wearing both a CGM and periodically sampling finger-prick blood glucose. CGM tracked capillary glucose closely, with the expected lag of about 15 minutes and a modest average underestimate of roughly 1.5 millimolar. During an 18-day monitoring window surrounding a full marathon, this athlete’s glucose spiked above 10 millimolar just before the start, peaked at 11.7 millimolar mid-race, and stayed elevated through the night, while easy practice runs kept glucose hovering near 5.4 millimolar.

The researchers are careful, refreshingly so, about what the data cannot prove. Internal physiological load was not measured; heart rate, power, and blood lactate went unrecorded, and pace was prescribed rather than verified during training. The authors acknowledge they cannot definitively attribute the competition-training difference to psychological stress rather than subtle differences in effort. A single bipolar pre-race questionnaire item on arousal showed no significant link to glucose, but the team itself argues the measure was inadequate, calling instead for validated instruments like the Competitive State Anxiety Inventory-2 and direct measurements of plasma or salivary catecholamines and cortisol.

The practical implications could reshape how endurance athletes prepare. Athletes whose glucose already soars before the gun may not need aggressive pre-race carbohydrate supplementation, suggesting individualized monitoring could personalize fueling strategies. Coaches might deliberately build competition-like stress into training sessions to acclimate athletes’ metabolism to the competitive milieu, since exogenous carbohydrate intake cannot reproduce the endocrine signature of real racing. And the sharp post-race glucose drop within an hour highlights a narrow recovery window when prompt glycogen replenishment matters most.

No athlete in the study experienced intra-race hypoglycemia despite the extraordinary glucose turnover, a reassuring finding given the high metabolic demands documented. The cohort’s limitations, all male, all collegiate, all from a single university squad, mean generalization to female athletes, masters competitors, or world-class Tier 4-5 performers requires caution. Yet the study stands as a proof of concept that wearable CGM technology can capture the metabolic fingerprint of competition itself, in the chaotic real world where athletic destinies are decided rather than in sanitized laboratory conditions. Future work pairing glucose data with heart rate variability, psychometric stress scales, and hormone sampling may finally untangle how much of the racing surge comes from the mind rather than the muscles.

Subject of Research: Interstitial glucose responses to sanctioned competition versus high-intensity training in highly trained male collegiate endurance athletes measured by continuous glucose monitoring

Article Title: Interstitial glucose during sanctioned competition and during high‐intensity training in highly trained collegiate male endurance athletes: A real‐world continuous glucose monitoring study

Article References: Kajisa, T., & Sakai, T. (2026). Interstitial glucose during sanctioned competition and during high‐intensity training in highly trained collegiate male endurance athletes: A real‐world continuous glucose monitoring study. Physiological Reports, 14(17), Article e71099. https://doi.org/10.14814/phy2.71099

Image Credits: AI Generated

DOI: 10.14814/phy2.71099

Keywords: continuous glucose monitoring, endurance athletes, competition stress, hepatic glucose output, catecholamines, exercise metabolism, running, race walking, glycogen, sports physiology, interstitial glucose, athletic performance