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

Falls are among the most consequential health events in later life. They are a leading cause of injury-related disability and death in older adults, and they trigger cascades of lost independence, hospitalization and rising care costs. Because falls are so common and so damaging, geriatric researchers have long searched for screening tools that can identify high-risk individuals before the first fracture or head injury occurs. Handgrip strength has been a centerpiece of this effort. Measured with a handheld dynamometer, it takes seconds, requires no specialized facility, and correlates with overall skeletal muscle strength better than almost any other single bedside test. International consensus frameworks for sarcopenia, the age-related loss of muscle mass and function, have accordingly adopted grip strength as a core diagnostic criterion, and the Asian Working Group for Sarcopenia, whose 2025 update the new study explicitly references, has been shifting emphasis from muscle mass toward muscle function.

Yet absolute grip strength has a stubborn statistical blind spot: body size. A taller, heavier person generally produces more absolute force than a smaller one, simply because larger bodies come with larger muscles. When a clinician compares a raw grip reading against a population cutoff, that reading conflates true muscular quality with sheer body dimensions. This is the same conceptual problem that plagued body weight measurements before body mass index normalized weight for height. The research team behind the new analysis reasoned that dividing grip strength by body mass index, expressed in kilograms of force per unit of BMI, would strip out the size confound and yield a cleaner index of relative muscle function, one that might track functional outcomes such as falls more faithfully than the raw number.

To test that hypothesis, the investigators turned to CHARLS, a nationally representative longitudinal survey of middle-aged and older Chinese residents. They anchored their analysis at the 2011 baseline wave, when muscle strength was assessed in thousands of participants, and then tracked self-reported falls during subsequent follow-up. Their analytic sample comprised 4,978 adults aged over the study’s older-adult range, split almost evenly between 2,510 men and 2,468 women. Baseline demographic variables and physician-confirmed chronic diseases were included as covariates in multivariable logistic regression models, allowing the team to isolate the independent contribution of each strength measure. During follow-up, 14.80 percent of the men and 22.37 percent of the women reported falling, a sex gap consistent with the international literature showing that older women fall, and are injured by falls, more often than older men.

The results split sharply along the line dividing absolute from adjusted strength. When handgrip strength was entered into the models as a continuous variable, each one-kilogram increase in absolute grip was associated with a 2.3 percent reduction in fall risk among men, with an odds ratio of 0.977 and a 95 percent confidence interval of 0.963 to 0.992, a statistically significant effect at P equals 0.003. Among women, however, absolute grip strength showed no significant association at all, with an odds ratio of 0.991 and a confidence interval spanning unity, from 0.975 to 1.008, at P equals 0.297. In other words, for the women in this cohort, the raw dynamometer reading carried essentially no predictive information about future falls once other factors were accounted for.

The BMI-adjusted ratio told a different and far more consistent story. Higher continuous HGS/BMI values were significantly associated with lower fall risk in both sexes, with nearly identical effect sizes: an odds ratio of 0.698 per unit increase in men, with a 95 percent confidence interval of 0.513 to 0.951 at P equals 0.023, and an odds ratio of 0.700 in women, with a confidence interval of 0.504 to 0.973 at P equals 0.034. The symmetry of these estimates is striking. Where absolute grip strength produced a significant result in one sex and a null result in the other, the adjusted index produced essentially the same protective association in both, suggesting that normalizing for body size removed a source of sex-specific distortion rather than introducing one.

Categorical analyses reinforced the pattern. When participants were grouped by conventional low versus high grip strength, men in the low-grip category showed a significantly elevated fall risk, with an odds ratio of 1.788 and a confidence interval of 1.354 to 2.360 at P below 0.001, but the corresponding association in women faded toward non-significance, with an odds ratio of 1.246 and a confidence interval of 0.966 to 1.608 at P equals 0.091. The decisive test came with quartile-based stratification of the HGS/BMI ratio. In that analysis, adults in the lowest quartile of BMI-adjusted grip strength remained independently and significantly more likely to fall than those in the highest quartile, in both men, with an odds ratio of 1.391 and a confidence interval of 1.015 to 1.905 at P equals 0.040, and women, with an odds ratio of 1.331 and a confidence interval of 1.006 to 1.762 at P equals 0.045. Across continuous and categorical modeling strategies alike, the adjusted index retained its predictive value where the absolute measure did not.

The mechanistic logic behind this divergence is worth unpacking. Falls are not caused by weak hands; they are caused by failures of the neuromuscular system to recover balance, by slow reaction times, by frailty and by the inability of leg and trunk muscles to generate force quickly enough. Grip strength works as a screening proxy precisely because it samples the same underlying physiology of age-related muscle decline. But when that proxy is expressed in absolute terms, a heavier older adult can post a respectable raw grip score while carrying a disproportionate burden of fat mass relative to functional muscle, a body-composition pattern sometimes described as sarcopenic obesity. That individual’s true functional reserve is worse than the raw number suggests, and the unadjusted measurement masks it. Dividing by BMI partially corrects for this, penalizing strength that is merely the product of a large frame and rewarding strength that is high relative to body size, which is closer to what balance recovery actually demands.

The clinical implications follow directly. Screening programs that use absolute grip cutoffs may systematically underestimate fall vulnerability in women and in smaller or heavier adults, precisely the groups in whom fall-related injuries are most devastating. The authors argue that HGS/BMI offers superior clinical utility and describe it as a rational conceptual extension of the evolving AWGS 2025 framework, which has been moving from muscle mass toward muscle function as the operative concept in sarcopenia care. Because the adjustment requires nothing more than a scale, a stadiometer and the dynamometer already in use, adopting the ratio imposes no additional cost or burden on busy clinics or community screening programs. A nurse could compute it on the spot.

Certain caveats temper the enthusiasm. The outcome was self-reported falling, which is vulnerable to recall error, and the cohort is Chinese, so cutoffs and associations may need recalibration in other populations and health systems. As with any observational cohort, residual confounding by unmeasured health conditions or activity levels cannot be excluded, and the published version was shared early as a citable accepted manuscript subject to further editorial refinement. Even so, the central message is robust and actionable: the same dynamometer reading becomes a better crystal ball when it is divided by body size. For a world with rapidly aging populations and enormous fall-related burdens, a free arithmetic step that rescues the predictive power of a thirty-second bedside test is the kind of quiet methodological upgrade that can ripple through screening guidelines, and through the lives of the older adults those guidelines protect.

Subject of Research: BMI-adjusted handgrip strength as a predictor of fall risk in older adults

Article Title: BMI-adjusted handgrip strength as a functional index to assess fall risk among older adults

Article References: Liu, L., Li, Z., Dai, Q., & Wu, Q. (2026). BMI-adjusted handgrip strength as a functional index to assess fall risk among older adults. BMC Geriatrics. https://doi.org/10.1186/s12877-026-08394-7

Image Credits: AI Generated

DOI: 10.1186/s12877-026-08394-7

Keywords: handgrip strength, body mass index, falls, older adults, sarcopenia, relative muscle strength, CHARLS, prospective cohort study, geriatrics, fall risk screening, muscle function, BMC Geriatrics

The rationale for targeting PKR was compelling. PKR, encoded by the EIF2AK2 gene, is canonically activated by double-stranded RNA during viral infection, but it can also be switched on by inflammatory signaling, oxidative stress, and ER stress, all of which are hallmarks of dystrophic muscle. Once active, PKR phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF2α) at serine 51, shutting down global protein synthesis, and it simultaneously amplifies inflammatory pathways through NFκB, MAPK, and the NLRP3 inflammasome. Prior work from the same research group had shown that PKR expression and activation are elevated in dystrophic skeletal muscle, and separate studies demonstrated that imoxin could alleviate ER stress in cultured muscle cells and suppress lipopolysaccharide-induced inflammation and atrophy gene expression in rodent muscle. The hypothesis was straightforward: if PKR is a driver of pathology, blocking it chronically should preserve muscle function and dampen disease progression.

To test this, researchers at Iowa State University and the University of Florida treated male C57BL/10 control mice and mdx mice beginning at eight weeks of age, injecting imoxin subcutaneously at 0.5 mg/kg five days per week for approximately 24 weeks, with vehicle-treated animals serving as controls. The dose and delivery route mirrored protocols that had successfully suppressed PKR activity in models of obesity, neuroinflammation, hypertension, and acute lung injury. At roughly 28 weeks of age, mice underwent in vitro functional testing of the costal diaphragm, the respiratory muscle that most faithfully reproduces the degenerative course of human DMD. Investigators measured isometric tetanic specific force, half-relaxation time, time to peak tension, and both dynamic and elastic passive forces across a range of stretches, providing a comprehensive mechanical portrait of each muscle before tissue was apportioned for histology and biochemical analysis.

The first surprise came at the molecular level. Western blot analysis revealed that dystrophin deficiency drove dramatic increases in total PKR and phosphorylated PKR at Thr446, along with a constellation of PKR regulatory proteins including PACT, phosphorylated PACT, PP1α, TRBP, and both total and phosphorylated eIF2α. Compared with vehicle-treated controls, mdx mice showed 180 to 300 percent higher levels of PKR and pPKR and 112 to 409 percent higher levels of eIF2α and peIF2α. Yet imoxin treatment changed none of these measures. Phosphorylated PKR remained just as elevated in drug-treated mdx mice as in their vehicle-treated counterparts, meaning the dosing strategy failed to achieve its primary biochemical objective of inhibiting PKR activation in the dystrophic diaphragm.

Functional testing told a similarly disappointing story. Specific force production was reduced by roughly 44 to 46 percent in mdx diaphragms regardless of treatment, half-relaxation time was prolonged by disease, and both dynamic and elastic passive forces, indicators of muscle stiffness, were significantly elevated in dystrophic muscle. Imoxin did not improve specific tension, relaxation kinetics, or time to peak tension in either healthy or dystrophic animals. The only flicker of benefit appeared in the histological data: trichrome staining showed that fibrosis occupied a dramatically larger fraction of mdx diaphragm than control tissue, a 477 to 564 percent increase, but imoxin reduced that fibrotic area by 18 percent in mdx mice. Intriguingly, this histological improvement was not accompanied by any reduction in the protein abundance of fibrosis drivers such as fibronectin, TGF-β1, or collagens I and III, all of which remained strongly elevated in drug-treated dystrophic muscle.

The broader signaling landscape was equally resistant to the drug. Endoplasmic reticulum stress markers, including BiP, the phosphorylated-to-total PERK ratio, ATF4, and spliced XBP1, were elevated 79 to 438 percent in mdx muscle, and imoxin left them untouched. Inflammatory signaling proteins told the same story: TLR4, MyD88, IKKα, total and phosphorylated NFκB, TNFα, pro- and cleaved IL-1β, and NLRP3 were all substantially increased by dystrophin deficiency, with TNFα rising nearly fourfold, and none of these measures differed between vehicle- and imoxin-treated mdx groups. The drug that had quieted inflammatory cascades in cell culture and in other disease models appeared powerless against the chronic, self-sustaining inflammatory milieu of the dystrophin-deficient diaphragm.

Why did imoxin fail where it had previously succeeded? The authors offer several technical and biological explanations. Pharmacologically, imoxin blocks the autophosphorylation of inactive PKR but may not strip phosphate groups from already-activated enzyme, and prior successes often involved acute inflammatory insults rather than lifelong, genetically driven stress. In cancer cachexia models, a fivefold higher dose of 5 mg/kg prevented muscle loss while 1 mg/kg did not, suggesting a therapeutic threshold that the 0.5 mg/kg regimen used here may not have reached. More fundamentally, the dystrophic intracellular environment appears poised to sustain PKR activation through multiple redundant inputs: chronic inflammation activates PACT, an upstream PKR kinase, while ER stress and oxidative stress provide additional activation routes that persist even without double-stranded RNA. The researchers observed that even endogenous inhibitors of PKR phosphorylation, TRBP and PP1α, were elevated alongside the activating signals, indicating that dystrophic muscle is differentially regulating the kinase but that the net balance favors activation, a situation the authors liken to the difficulty of pharmacologically inhibiting calpain in dystrophic muscle.

The study’s implications cut both ways. On one hand, it is a negative result: a widely used PKR inhibitor, delivered chronically at a dose validated in other contexts, does not attenuate disease severity in the dystrophic diaphragm of male mice. On the other hand, the consistent, coordinated upregulation of PKR alongside ER stress and inflammatory markers reinforces the kinase’s status as a potential central regulatory node in DMD pathology. The authors suggest that future strategies might bypass autophosphorylation altogether, instead preventing activators from engaging PKR or enhancing its endogenous inhibitors, approaches that could prove more effective against a kinase embedded in such a densely interconnected stress-signaling web. Whether higher imoxin doses, alternative inhibitors, or combination therapies could succeed remains an open question, as does whether female mdx mice, which experience a milder phenotype, would respond differently.

For the DMD research community, the work is a reminder that respiratory muscle, the ultimate arbiter of patient survival, presents a uniquely hostile pharmacological environment. The diaphragm of the mdx mouse endures decades of contraction against a fibrotic, inflamed, calcium-dysregulated substrate, and interventions that succeed in limb muscle or in acute injury models may simply be overwhelmed there. As clinical trials of gene therapies, exon skipping, and anti-inflammatory agents continue to reshape the DMD treatment landscape, this study tempers expectations for stress-kinase inhibitors while sharpening the field’s understanding of why dystrophic muscle is so difficult to quiet. PKR remains a suspect worth pursuing, but catching it, the findings suggest, will require more than blocking a single phosphorylation site.

Subject of Research: PKR inhibition with imoxin and disease progression in the dystrophic diaphragm of mdx mice, a model of Duchenne muscular dystrophy

Article Title: Long‐term imoxin treatment does not attenuate disease severity in dystrophic diaphragm of male mice

Article References: Lee, J. H., Vorwald, M. E., Roths, M., Selsby, J. T., & Valentine, R. J. (2026). Long‐term imoxin treatment does not attenuate disease severity in dystrophic diaphragm of male mice. Physiological Reports, 14(18), Article e71115. https://doi.org/10.14814/phy2.71115

Image Credits: AI Generated

DOI: 10.14814/phy2.71115

Keywords: Duchenne muscular dystrophy, mdx mice, protein kinase R, imoxin, diaphragm, ER stress, inflammation, fibrosis, muscle function, eIF2alpha, NFkB, integrated stress response