Exercise would seem the obvious countermeasure, but for many elderly people it is simply impractical. Fear of injury and falling, preexisting health conditions, lack of motivation, and financial costs all act as potent deterrents. Even when resistance exercise is possible, an age-related phenomenon called anabolic resistance blunts the muscle’s response to both exercise and nutrition, limiting the efficacy of conventional interventions. Disuse itself worsens the problem, since even acute immobilization suppresses the protein synthesis machinery needed for recovery once movement resumes. Existing countermeasures, including neuromuscular electrical stimulation, protein and amino acid supplementation, beta-hydroxy-beta-methylbutyrate, and omega-3 fatty acids, have largely failed to preserve both muscle strength and physical function in older adults during immobilization.

Against this discouraging backdrop, a new study published in Physiological Reports offers a strikingly different approach: harnessing molecules produced by the gut microbiome during exercise. Researchers previously identified pipecolic acid and succinate, two so-called microbial-derived exerkines, as metabolites whose oral co-administration prevented disuse-induced muscle atrophy and preserved muscle function in adult mice. Exerkines are signaling molecules released in response to exercise, and the discovery that some of them originate from gut microbes has opened an entirely new frontier in muscle biology. The question was whether these compounds could also protect the far more vulnerable muscles of aged animals.

To find out, a team at the University of Kentucky used 22- to 25-month-old male and female C57BL/6JN mice from the National Institute on Aging aged rodent colony, animals roughly equivalent in biological terms to elderly humans. Each mouse underwent ten days of unilateral hindlimb casting, with one limb enclosed in a 3D-printed plastic cast in gentle flexion at the knee and dorsiflexion at the ankle while the contralateral limb remained free as an internal control. Throughout the immobilization period, the mice received either a vehicle solution of 2 percent sucrose or a combination of pipecolic acid and succinate, delivered at approximately 190 and 95 milligrams per kilogram per day respectively, via their drinking water.

After the casting period, the researchers evaluated the soleus, plantaris, and gastrocnemius muscles for mass, histological fiber morphology, ex vivo contractile function, and mitochondrial content. The results revealed a nuanced, partial protection. Whole-muscle mass was largely unchanged in the soleus and plantaris, but PAS-treated mice retained a significantly greater proportion of gastrocnemius mass in the casted limb, 90.0 percent versus 85.2 percent of the contralateral control limb, irrespective of sex. The gastrocnemius is the largest of the three muscles and sustains the greatest absolute mass loss during casting, which may explain why the protective effect was most detectable there. The failure to protect soleus and plantaris mass mirrors the broader literature, in which even the most intensively studied protein supplementation strategies have failed to prevent muscle loss during bed rest or limb immobilization in older adults.

At the level of individual muscle fibers, however, the story was considerably more encouraging. Mean fiber cross-sectional area was preserved in both the soleus and the plantaris of PAS-treated mice. In the soleus, the effect was sex-specific: PAS-treated females retained larger mean fiber areas than vehicle-treated females, with the same pattern evident in Type I fibers, whereas males showed no treatment difference. For Type IIa fibers there was a main effect of treatment favoring PAS across both sexes, though a trending interaction suggested females drove much of the effect. Notably, the protection extended to the plantaris, a predominantly fast, glycolytic muscle, even though succinate is known to promote an oxidative, slow-fiber program via SUCNR1 signaling. This suggests the fiber-level benefit is not confined to oxidative fibers and cannot be explained solely by succinate-driven oxidative remodeling, pointing to a possible contribution from pipecolic acid, whose actions in skeletal muscle remain largely uncharacterized.

The functional data were the most striking of all, and they diverged sharply by sex. In ex vivo tests of the casted soleus, PAS-treated females produced greater absolute force across the entire stimulation frequency range from 10 to 120 hertz, and developed force more rapidly, than vehicle-treated females. Males showed no such improvements in force or rate of force development. Instead, PAS-treated males demonstrated markedly higher fatigue resistance across 150 repeated contractions, sustaining a greater proportion of their initial force, while females showed no treatment effect on this measure. This outcome-dependent, sexually dimorphic pattern suggests that the two metabolites may influence different aspects of muscle physiology in males and females, a coherence that extends across morphological and functional outcomes alike.

One clue to the mechanism came from measurements of citrate synthase activity, a standard index of mitochondrial content, in the casted gastrocnemius. PAS-treated females exhibited significantly greater citrate synthase activity than vehicle-treated females, with no corresponding difference in males, paralleling the female-specific preservation of fiber size and force. Whether greater mitochondrial content actually causes the preservation of fiber size and force in females, or merely accompanies it, cannot be resolved from this study, but oxidative capacity now stands out as a prime target for mechanistic investigation. In males, the improved fatigue resistance without increased citrate synthase activity hints that succinate, a well-studied mitochondrial substrate and signaling metabolite, may have acted through mitochondrial function or substrate supply rather than by expanding mitochondrial content. Fatigue resistance is closely linked to oxidative capacity, mitochondrial function, and calcium handling within the muscle fiber, making succinate a compelling candidate for the male-specific benefit.

The clinical significance of these findings is hard to overstate. Neuromuscular electrical stimulation, though widely applied, produced no improvement in maximal strength, fiber cross-sectional area, or stair-climbing power in elderly postoperative patients over twelve weeks in one trial. Even when electrical stimulation is combined with protein supplementation during bed rest, functional deficits persist in older adults despite maintained muscle mass. Against this record of failure, a simple oral supplement of two microbial metabolites that preserves fiber size and contractile function in aged muscle represents a genuinely novel therapeutic avenue. It is particularly notable that females, who appear more susceptible to disuse atrophy and greater strength losses during immobilization, showed the strongest morphological and force-related responses to treatment.

Important caveats remain. The study was largely confined to phenotypic and functional outcomes, and the single index of mitochondrial content cannot resolve the molecular pathways through which pipecolic acid and succinate act. The effects on food intake and body composition were not assessed, only the casted soleus was tested ex vivo, and disuse itself is known to alter the gut microbiome, raising the possibility that age and disuse interact to lower endogenous availability of these very metabolites. Future work must also test whether the compounds enhance recovery during post-immobilization rehabilitation, and whether doses can be optimized across ages and sexes. Still, the message is clear: exercise’s chemical conversation with our gut microbes may hold the key to protecting aging muscles when movement itself is impossible, and any such therapy must be designed with sex as a primary biological variable from the outset.

Subject of Research: Microbial-derived exerkines and disuse-induced muscle atrophy in aged mice

Article Title: Microbial‐derived Exerkines preserve muscle size and function during disuse in aged mice in a sex‐dependent manner

Article References: Microbial‐derived Exerkines preserve muscle size and function during disuse in aged mice in a sex‐dependent manner. (n.d.). https://doi.org/10.14814/phy2.71137

Image Credits: AI Generated

DOI: 10.14814/phy2.71137

Keywords: exerkines, gut microbiome, pipecolic acid, succinate, sarcopenia, disuse atrophy, skeletal muscle, aging, sex differences, mitochondria, muscle function, immobilization

The investigation began in the clinic. The researchers measured serum IGFBP7 levels in patients with sepsis admitted to the Second Affiliated Hospital of Anhui Medical University and compared them with healthy controls. The results were striking: patients with sepsis showed markedly elevated circulating IGFBP7, and those levels correlated positively with serum creatinine, blood urea nitrogen, alanine aminotransferase, and aspartate aminotransferase, the standard laboratory markers of kidney and liver dysfunction. In other words, the more IGFBP7 a patient carried in their bloodstream, the worse their organs appeared to be faring. This clinical signal set the stage for a deeper mechanistic dive using animal models.

Turning to mice, the team used the cecal ligation and puncture model, a widely used experimental simulation of septic shock in which the cecum is perforated to release fecal bacteria into the abdominal cavity. As in humans, IGFBP7 surged in the serum and urine of septic mice, and Western blot analysis revealed upregulation of the protein in the kidneys, liver, and lungs. Immunofluorescence staining pinpointed the cellular sources: proximal tubular epithelial cells in the kidney and hepatocytes in the liver. Cultured mouse tubular epithelial cells and hepatocytes exposed to lipopolysaccharide, the toxic component of bacterial outer membranes, likewise ramped up IGFBP7 production, confirming that the response is cell-autonomous rather than a secondary artifact of systemic illness.

The decisive experiment came from genetics. The researchers generated mice lacking the Igfbp7 gene entirely, as well as organ-specific knockout lines in which the gene was deleted only in renal tubular epithelial cells or only in hepatocytes. When subjected to sepsis, the global knockout mice survived at significantly higher rates than their wild-type littermates. Their kidneys, livers, and lungs showed dramatically less injury: lower creatinine and BUN, reduced liver enzymes, less alveolar septal thickening and capillary congestion in the lungs, and blunted activation of NF-κB, the master transcriptional switch of inflammation. Proinflammatory cytokines such as tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6 were all substantially tamped down. The tissue-specific knockouts confirmed that IGFBP7 acts locally within each organ, not merely as a circulating signal.

To understand how a secreted binding protein could wreak such havoc inside cells, the team performed an unbiased proteomic hunt. Using co-immunoprecipitation followed by liquid chromatography-tandem mass spectrometry, they pulled down proteins that physically associate with IGFBP7 in septic kidney tissue. The top candidate was oxoglutarate dehydrogenase, or OGDH, a critical enzyme in the tricarboxylic acid cycle that catalyzes the conversion of alpha-ketoglutarate to succinyl-CoA, a direct precursor of succinate. The interaction was confirmed in the kidneys, liver, and lungs of septic mice, and high-resolution confocal microscopy showed IGFBP7 and OGDH co-localizing inside stressed cells. Subcellular fractionation revealed that IGFBP7, though classically considered a secreted protein, can be internalized by cells and detected in the mitochondrial fraction where OGDH resides. Molecular docking and truncation experiments mapped the binding interface to the Kazal-like and immunoglobulin-like C2-type domains of IGFBP7.

The functional consequences of this interaction proved to be a story about a chemical modification called lysine succinylation. Succinyl-CoA can covalently attach succinate groups to lysine residues on target proteins, altering their conformation and activity, and the mitochondrial enzyme SIRT5 normally acts as a desuccinylase that keeps this modification in check. The researchers found that during sepsis, the association between OGDH and SIRT5 was weakened, and IGFBP7 overexpression further disrupted this partnership. The result was a marked increase in overall OGDH succinylation, which coincided with enhanced OGDH enzymatic activity and a flood of succinate in the serum and kidney tissue. Consistent with this chain of events, serum succinate levels in mice correlated positively with IGFBP7, creatinine, ALT, and interleukin-1 beta, tying the metabolic shift directly to organ injury and inflammation.

Causality was tested in both directions. First, the team showed that succinyl phosphonate, a specific inhibitor of OGDH, reduced the expression of the kidney injury marker KIM-1 and NF-κB phosphorylation in stressed cells, implicating OGDH activity in the damage pathway. Second, and more compellingly, they administered dimethyl succinate, a cell-permeable succinate ester, to Igfbp7 knockout mice undergoing sepsis. Restoring succinate levels largely erased the protective phenotype: kidney and liver function markers climbed, tubular injury and macrophage infiltration worsened, and lung dysfunction partially returned. A parallel rescue in cultured cells produced the same outcome. Together, these experiments establish succinate accumulation as a critical downstream mediator through which IGFBP7 inflicts its damage.

The downstream target of all this succinate is the mitochondrion itself. Excessive succinate is known to disrupt redox balance, drive reactive oxygen species production through complex II of the electron transport chain, and destabilize HIF-1 alpha to amplify interleukin-1 beta expression. In this study, lipopolysaccharide-treated cells with high IGFBP7 showed depressed oxygen consumption, depleted ATP, reduced mitochondrial DNA copy number, fragmented and rounded mitochondria, collapsed membrane potential, and oxidative stress. Silencing Igfbp7 reversed essentially all of these defects, restoring elongated mitochondrial networks, membrane potential, and energy production. In septic mice, Igfbp7 deficiency preserved mitochondrial ultrastructure as visualized by transmission electron microscopy, rebalanced fission and fusion protein expression, and reduced oxidative damage markers across the kidneys, liver, and lungs.

Perhaps the most clinically exciting finding is that the damage is pharmacologically reversible. A neutralizing antibody against IGFBP7, administered immediately after sepsis induction and again twelve hours later, lowered circulating IGFBP7 and succinate, reduced inflammatory cytokines, and significantly improved kidney, liver, and lung function in septic mice. Tissue histology showed less injury and fewer infiltrating macrophages in all three organs, and mitochondrial dynamics and biogenesis markers in the kidney normalized. The treatment also attenuated senescence-associated changes, reducing p16 and p21 expression and senescence-associated beta-galactosidase activity in renal tissue, consistent with IGFBP7’s established role as a component of the senescence-associated secretory phenotype.

The authors are careful to note the limitations. The evidence rests primarily on young male mice and a small clinical cohort, the cecal ligation and puncture model cannot fully capture the heterogeneity of human sepsis, and the precise lysine residues on OGDH whose succinylation drives its hyperactivity remain unidentified. How IGFBP7 enters cells and reaches the mitochondrial compartment is also unresolved. Still, the study delivers a coherent and testable model: sepsis elevates IGFBP7, which penetrates cells and displaces SIRT5 from OGDH, unleashing succinate production that poisons mitochondria and ignites inflammatory injury across multiple organs. With IGFBP7 inhibitors already under investigation for kidney disease and fibrosis, the prospect of translating this axis into a therapy for sepsis-induced multiple organ dysfunction no longer seems remote, and a protein once regarded as a mere biomarker may soon become a treatment target in one of medicine’s most urgent battles.

Subject of Research: The role of IGFBP7 and OGDH-mediated succinate accumulation in sepsis-induced multiple organ dysfunction

Article Title: IGFBP7 promotes sepsis-induced multiple organ dysfunction by enhancing OGDH-mediated succinate accumulation

Article References: Xie, S.-S., Dong, Y.-H., Xu, L., Dong, Z.-H., Gao, Y.-Y., Li, W., Ma, W.-X., Ru, Y.-X., Zhao, T., Hou, R., Zhang, L.-X., Yang, Q., Jin, J., Wen, J.-G., & Meng, X.-M. (2026). IGFBP7 promotes sepsis-induced multiple organ dysfunction by enhancing OGDH-mediated succinate accumulation. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2026.09.013

Image Credits: AI Generated

DOI: 10.1016/j.jare.2026.09.013

Keywords: sepsis, IGFBP7, OGDH, succinate, mitochondrial dysfunction, multiple organ dysfunction syndrome, SIRT5, succinylation, inflammation, NF-kB, acute kidney injury, therapeutic target

The commercial stakes are considerable. The global organic acids market is projected to reach 36.86 billion dollars by 2026, and in 2004 the United States Department of Energy identified twelve high-priority building-block chemicals obtainable from biomass, roughly seventy percent of which are organic acids. These include succinic acid, 3-hydroxypropionic acid, itaconic acid, and levulinic acid, compounds that serve as precursors for biodegradable plastics, solvents, pharmaceuticals, and food additives. Traditionally these chemicals come from petrochemical synthesis or heterotrophic fermentation, both of which carry substantial carbon footprints. Cyanobacteria offer a third route: photoautotrophic biosynthesis that consumes the greenhouse gas responsible for climate change as its raw material.

The metabolic logic behind this capability is elegant. Cyanobacteria fix atmospheric carbon dioxide through the Calvin-Benson-Bassham cycle, generating central intermediates such as pyruvate, phosphoenolpyruvate, and acetyl-CoA that feed into the tricarboxylic acid cycle. From these nodes, carbon can be channeled into acetate, lactate, citrate, succinate, fumarate, and malate. Intriguingly, cyanobacteria possess an atypical, incomplete TCA cycle lacking the canonical 2-oxoglutarate dehydrogenase complex. Instead, they bypass this step via 2-oxoglutarate decarboxylase and succinic semialdehyde dehydrogenase, an evolutionary adaptation that appears designed to preserve carbon skeletons for biosynthesis rather than burning them off as carbon dioxide. Some strains also harbor the glyoxylate shunt and a gamma-aminobutyric acid shunt, alternative routes that connect carbon metabolism with nitrogen assimilation and redox regulation.

The organisms also display a striking diurnal rhythm that researchers are learning to exploit. During daylight, cyanobacteria assimilate carbon dioxide into glycogen stores; when darkness falls and oxygen dwindles, they ferment these reserves, secreting organic acids and hydrogen. Under dark, anoxic conditions, Synechocystis sp. PCC 6803 has been shown to release more than 400 milligrams per liter of acetate, along with lactate, succinate, and malate, independent of nitrogen source. This natural overflow metabolism acts as a redox-balancing mechanism, dumping excess reducing equivalents when the cell’s usual sinks, such as glycogen and protein synthesis, are unavailable. Engineers are now working to redirect this flux deliberately toward single target products under continuous illumination.

Case studies demonstrate how far metabolic engineering can push these yields. In Synechocystis PCC 6803, inserting a codon-optimized phosphoketolase from Pseudomonas aeruginosa boosted acetate production fortyfold, and co-expressing phosphotransacetylase raised titers to 2.3 grams per liter, an eightyfold increase over the starting strain. Lactate engineering has been even more dramatic: combining overexpression of malic enzyme and d-lactate dehydrogenase with deletion of the acetate kinase gene produced a record 26.6 grams per liter of d-lactate from high-density cell cultures after seventy-two hours of fermentation. Because lactate is the monomer for polylactic acid, a biodegradable plastic used in packaging and 3D printing, such strains could eventually supply the bioplastics industry with carbon-negative feedstock.

Succinate, a top Department of Energy platform chemical used to make 1,4-butanediol, gamma-butyrolactone, and biodegradable polymers, has seen similar success. In Synechococcus elongatus PCC 7942, researchers used CRISPR interference to repress glycogen synthesis and succinate dehydrogenase while overexpressing key carboxylation and decarboxylation enzymes, achieving the highest cyanobacterial succinate titer reported to date: 4.8 grams per liter in twenty-eight days, rising to 8.9 grams per liter with reinoculation. A separate photomixotrophic strategy engineered the same strain to import glucose at low pH and export succinate at high pH, exploiting opposing proton symporters to reach 5.0 grams per liter in ten days. Even citrate, long considered too tightly regulated to accumulate, has been produced photoautotrophically in PCC 7002 using a theophylline-responsive riboswitch to throttle TCA flux, yielding more than a hundredfold increase over wild type.

Redox engineering has emerged as a central theme in these efforts. Cyanobacteria inherently produce abundant NADPH through photosynthesis, yet many fermentative enzymes prefer NADH, creating a cofactor mismatch that limits yields. Solutions include overexpressing transhydrogenases such as PntAB to interconvert the two pools, and site-directed mutagenesis to swap enzyme cofactor preferences, as demonstrated with an NADH-dependent lactate dehydrogenase from Lactobacillus bulgaricus that was redesigned to accept NADPH. Environmental tuning matters too: raising cultivation temperature from 30 to 37 degrees Celsius enhanced d-lactate and succinate production in PCC 6803, while mildly acidic conditions increase passive secretion of weak acids by boosting membrane permeability. Nitrogen starvation can push glycogen-deficient strains into a photo-catalytic state, continuously excreting alpha-ketoglutarate and pyruvate even without growth.

Formidable obstacles remain before these microbes can compete with petrochemical plants. Cyanobacteria grow slowly, allocate only a minor fraction of fixed carbon to target products, and suffer from genetic instability, low transformation efficiency, and byproduct formation as carbon leaks into competing pathways. Product recovery is another bottleneck: organic acids exist in ionized form at neutral pH, and traditional acidification with mineral acids generates mountains of inorganic salt waste. Photobioreactors struggle with uneven light penetration, limited gas transfer, and biofouling, and techno-economic and life-cycle assessments for engineered cyanobacterial systems remain scarce, making it difficult to judge commercial feasibility. Most studies to date remain at proof-of-concept or laboratory scale.

The road ahead is nonetheless rich with opportunity. Emerging tools include CRISPR-based gene repression and activation, riboswitches and light-inducible promoters that decouple growth from production, and adaptive laboratory evolution to breed acid-tolerant strains. Machine learning-guided flux modeling and multi-omics integration are converting strain design from trial-and-error into predictive optimization, while next-generation photobioreactors with optical waveguides and gas-permeable membranes promise better scalability. Co-cultures with heterotrophs, photomixotrophy using waste-derived carbon, and multi-product biorefineries coupling organic acids with biofuels and bioplastics could further improve economics. Greener recovery technologies, including membrane filtration, electrodialysis, and in situ product removal, are being developed to replace salt-generating acidification. If these threads converge, cyanobacteria could transform sunlight and carbon dioxide into the molecular backbone of a circular, fossil-free chemical economy, turning the planet’s oldest oxygen-makers into its newest industrial workhorses.

Subject of Research: Metabolic engineering of cyanobacteria for sustainable photosynthetic production of organic acids

Article Title: Advances in organic acid production using cyanobacteria: strategies and applications

Article References: Pathania, R., & Srivastava, A. (2025). Advances in organic acid production using cyanobacteria: strategies and applications. Blue Biotechnology, 2(1), Article 22. https://doi.org/10.1186/s44315-025-00045-7

Image Credits: AI Generated

DOI: 10.1186/s44315-025-00045-7

Keywords: cyanobacteria, organic acids, metabolic engineering, synthetic biology, carbon dioxide fixation, succinate, lactate, TCA cycle, bioplastics, photobioreactors, CRISPRi, sustainable biomanufacturing