bims-ensmum 2026-09-13 papers

JCI Insight. 2026 Sep 10. pii: e210523. [Epub ahead of print]

Feeding-induced muscle mTORC1 signaling regulates postprandial protein synthesis and endurance but not muscle size.

Samuel C Lapp, Krystle C Kalafut, Madi Y Cissé, Khaled Tighanimine, Dean M Rosenthal, Will Doxsey, Sheng Hui, Karen E Inouye, Claire E Morrow, Yann Cormerais, Brendan D Manning.

Activation of the mechanistic target of rapamycin (mTOR) complex1 (mTORC1) promotes muscle protein synthesis, mass, and function. Muscle mTORC1 can be activated by feeding and contraction. Here, muscle mTORC1 signaling, protein synthesis, mass, and function are characterized in a genetic mouse model that separates these two major modes of muscle mTORC1 regulation. AKT signaling is required for feeding-induced muscle mTORC1 signaling and protein synthesis, and mice expressing a mutant of tuberous sclerosis complex 2 (TSC2) that cannot be phosphorylated by AKT specifically in skeletal muscle (SkM-TSC2-5A) attenuate these effects of feeding. Despite this loss of postprandial protein synthesis, SkM-TSC2-5A mice have similar muscle and myofiber size compared to SkM-TSC2-WT mice. SkM-TSC2-5A mice maintain normal muscle mTORC1 activation in response to contraction and exhibit no differences in atrophy-related gene expression or ribosomal content. SkM-TSC2-5A mice exhibit improved maximal endurance capacity without changes in muscle contractile function. This phenotype occurs without alterations in muscle glycogen content or myofiber type but does coincide with a modest increase in muscle mitochondrial content. Therefore, AKT-mediated phosphorylation of TSC2 is required for postprandial mTORC1 activation and the induction of protein synthesis; however, these are dispensable for the development and maintenance of muscle mass in sedentary mice.

Keywords: Endocrinology; Muscle biology; Signal transduction

DOI: https://doi.org/10.1172/jci.insight.210523

J Physiol. 2026 Sep 11.

Preserved mitochondrial respiration in presence of oxidative stress and reduced mitochondrial mass after 10-day bed rest in older adults.

Evgeniia Motanova, Lucrezia Zuccarelli, Evgenii Lysenko, Stefano Amoretti, Marco Pirazzini, Ornella Rossetto, Lorenza Brocca, Roberto Bottinelli, Maria Antonietta Pellegrino, Giovanni Baldassarre, Clarissa Gissi, Giovanna Lippe, Mladen Gasparini, Boštjan Šimunic, Rado Pišot, Bruno Grassi, Marco V Narici.

Ageing affects mitochondrial integrity in skeletal muscle, and physical inactivity may further exacerbate these changes. Although mitochondrial alterations are documented in ageing and disuse independently, how disuse impacts the mitochondrial phenotype in older populations remains unclear. This work aimed to characterise how physical inactivity impacts mitochondrial function, morphology and gene expression in the skeletal muscle of older adults. Ten healthy older men (65+ years) underwent 10 days of bed rest. Skeletal muscle biopsies were collected before and after bed rest to assess mitochondrial respiration (high-resolution respirometry), H2O2 emission, mitochondrial protein expression, morphology and volume density (electron microscopy) and transcriptomic profile. Ten days of inactivity increased mitochondrial reactive oxygen species (ROS) emission under non-phosphorylating conditions but did not impair oxidative phosphorylation (OXPHOS) capacity, indicating preserved respiratory efficiency. Consistently, mitochondrial respiratory complex and supercomplex protein abundance were unchanged. Mitochondrial mass decreased, as shown by reduced mitochondrial volume density. Reduced dynamin-like protein 1 (DRP1) phosphorylation at serine 637 was observed, whereas other mitochondrial fission and fusion protein levels remained unchanged. Mitochondrial morphology remained unaltered. Transcriptomic analysis revealed >3000 differentially expressed genes, characterised by downregulation of oxidative phosphorylation genes alongside altered mitophagy, antioxidant and oxidoreductase pathways. In summary, 10-day bed rest increased mitochondrial ROS emission and reduced mitochondrial mass in older skeletal muscle despite preserved respiratory function, indicating that elevated ROS production occurs upstream of respiratory dysfunction and is potentially linked to impaired antioxidant defence and ROS clearance. These findings suggest that preserving redox balance during inactivity may be a key strategy to maintain muscle health and functional independence in ageing populations. KEY POINTS: The impact of short-term physical inactivity on mitochondrial function within the context of ageing remains poorly defined. This study examined the impact of 10-day bed rest on skeletal muscle mitochondrial function, morphology and gene expression in older adults. Short-term inactivity increased mitochondrial ROS production, accompanied by a dysregulation of antioxidant and oxidoreductase genes, indicating a reduced capacity for ROS clearance. Mitochondrial respiration was preserved under both submaximal and maximal stimulation. When normalised to mitochondrial content (citrate synthase activity), respiratory capacity increased, suggesting improved intrinsic efficiency. Mitochondrial mass was reduced, supported by decreased mitochondrial volume density assessed morphologically. Transcriptomic alterations in the mitophagy pathway suggest a potential role of altered mitochondrial degradation in this reduction. These findings indicate a transient compensatory response of ageing mitochondria to short-term disuse, suggesting that functional impairments are likely driven by cardiovascular and microvascular factors rather than mitochondrial respiration itself.

Keywords: OXPHOS; ROS; inactivity; mitochondria; mitochondrial dynamics; oxidative metabolism

DOI: https://doi.org/10.1113/JP291588

PLoS One. 2026 ;21(9): e0357952

Reliability of biochemical assays of nitric oxide biomarkers in human skeletal muscle tissue samples.

Raghini Rajaram, Matthew I Black, Chenguang Wei, Andrew M Jones, Paul G Winyard, Anni Vanhatalo.

Accurate measurements of nitrate and nitrite concentrations in human skeletal muscle are fundamental to further our understanding of their role in nitric oxide (NO) homeostasis. We investigated the effects of saline wash and immediate processing with a potassium ferricyanide-containing nitrite-preserving stop solution (to remove the effects of haemoglobin from blood surrounding the tissue) on human skeletal muscle nitrate and nitrite concentrations. Skeletal muscle tissue was collected from 24 healthy adults and processed with and without saline wash, and with and without stop solution. Tissue samples (n = 17) washed in saline had significantly lower nitrate concentration (p < 0.01) and lower inter-sample variability (45 ± 23 nmol/g) compared to tissue samples not washed in saline (104 ± 52 nmol/g), with no correlation and high bias (-59 ± 49 nmol/g) between the two methods. Nitrite concentration was not significantly different between tissue samples washed in saline (1.94 ± 0.90 nmol/g) and samples not washed in saline (1.55 ± 0.86 nmol/g), with no correlation and minimal bias (0.39 ± 0.85 nmol/g) between the two methods. Addition of nitrite-preserving stop solution did not result in significant differences in concentrations of nitrate or nitrite. In summary, although our study is limited by the lack of Hb and Mb measurements, saline washing of biopsied tissue samples improved the reliability of nitrate and nitrite concentrations measured in human skeletal muscle.

DOI: https://doi.org/10.1371/journal.pone.0357952

Aging Cell. 2026 Sep;25(9): e70704

Sustained Activation of CaMKII Promotes Skeletal Muscle Contractile Dysfunction in Aging.

Michael R Bene, Tae Chung, Elizabeth D Luczak, Gabriel Lopez-Cecetaite, William A Fountain, Giovanni Rosales-Soto, Erick Hernández-Ochoa, Corina Antonescu, Liliana Florea, Seeun J Jeong, Emily Elassal, Anne Le, Qian-Li Xue, Ahmet Hoke, Peter M Abadir, Qinchuan Wang.

Sarcopenia, the age-related loss of muscle strength and mass, contributes to adverse health outcomes in older adults. Exercise engages calcium (Ca2+)- and redox-dependent signaling pathways that enhance muscle performance and adaptation, whereas aging disrupts Ca2+ and redox homeostasis. CaMKII is a key transducer of both signals, raising the possibility that sustained CaMKII signaling becomes maladaptive with aging. Here, we show that CaMKII protein abundance is increased in aged mouse skeletal muscle and that sustained CaMKII activation in young muscle is sufficient to impair contractile function before substantial atrophy develops and, with prolonged activation, to promote progressive muscle loss. Sustained CaMKII activation also disrupted mitochondrial organization and shifted the young-muscle transcriptome toward an aged profile characterized by inflammatory and stress-response pathways. Inhibiting canonical NF-κB signaling partially preserved contractile force during prolonged CaMKII activation without preserving muscle mass, and mediation analysis implicated heme/iron-related transcriptional remodeling in the muscle-mass-independent decline in force. Conversely, expression of CN19o, a peptide inhibitor of CaMKII, in aged muscle improved contractile function and shifted the transcriptome away from an aging-associated profile without inducing hypertrophy. Together, these findings identify sustained CaMKII signaling as a contributor to age-associated muscle dysfunction and support a context-dependent shift from adaptive CaMKII signaling in youth to maladaptive signaling in aging, consistent with antagonistic pleiotropy.

Keywords: calcium signaling; calcium‐calmodulin‐dependent protein kinase type 2; muscle weakness; oxidative stress; sarcopenia; skeletal muscle

DOI: https://doi.org/10.1111/acel.70704

Curr Dev Nutr. 2026 Sep;10(9): 109460

Influence of Protein Intake during Obesity Reduction on Physical Function and Body Habitus in Older Males with Prediabetes: A Pilot Study.

Connie W Bales, Marshall G Miller, Shelley R McDonald, Jessica T Wallis, Leigh Ann Yeager, Richard J Sloane, Kathryn N Porter Starr.

Background: Weight loss can improve health and function in older adults with obesity but may also accelerate loss of fat-free mass. Older men are underrepresented in obesity intervention trials; thus we tested higher protein intake plus exercise to help preserve muscle mass and physical function during weight loss in men with obesity and prediabetes.
Objectives: We evaluated the effects of an enhanced protein weight loss intervention relative to a recommended dietary allowance (RDA)-level protein intervention in older males (veterans) with prediabetes and obesity.
Methods: This study was a randomized controlled trial. Equal numbers of participants, males aged >55 y with obesity [body mass index (BMI), in kg/m2> 30] and prediabetes, were randomly assigned to either an RDA protein (0.8 g/kg/d; n = 32) or an enhanced protein (1.4 g protein/kg/d with 30 g high-quality protein 4 times/d; n = 32) hypocaloric diet plus exercise intervention, with outcome assessments at 3 and 6 mo., namely, Short Physical Performance Battery (SPPB) and fat-free mass (FFM) measured by Bodpod, body weight, body fat, waist circumference, 6-min walk time test (6MWT), 8-foot up-and-go test, and handgrip strength.
Results: Baseline characteristics were as follows: BMI = 35.8 ± 4.3, mean age 67.6 ± 7.0 y, and hemoglobin A1c 6.0% ± 0.3%. For the SPPB score, the Enhanced Protein group had a greater benefit at both 3 mo (small Cohen's d = 0.23) and at 6 mo (moderate Cohen's d = 0.68). The Enhanced Protein group showed an increase in SPPB at 3 mo of 1.5 ± 0.2 units, compared with 1.2 ± 0.3 units for the RDA Protein group. The amount of weight lost was also more in the Enhanced Protein group at 3 mo (4.7% ± 0.9 compared with 3.1% ± 0.7). Additionally, participants in the Enhanced Protein group preserved more FFM at 6 mo (moderate group effect, Cohen's d = 0.48; 95% confidence interval [CI]: 0.26, 0.62), with a loss of 0.8 ± 0.3 kg compared with the RDA Protein arm, who lost 1.5 ± 0.4 kg. Other Enhanced Protein group effects at 3 mo included an increased distance walked in the 6MWT by 63.3 ± 12.8 m [mean difference (MD): 29.0 m; d = 0.53; 95% CI: <0, 1.19] and increased handgrip strength by 3.7 ± 1.2 kg (MD: -2.8 kg; d = 0.56; 95% CI: 0.21, 0.88), relative to the RDA Protein group, which had increases of 34.4 ± 11.9 m and 0.8 ± 1.0 kg for 6MWT and handgrip strength, respectively. The handgrip effect remained at 6 mo for Enhanced Protein, with an increase of 3.0 ± 1.5 kg compared with an increase of 1.2 ± 1.4 kg in RDA Protein (MD: -1.8; d = 0.30; 95% CI: 0.15, 0.35).
Conclusions: The results provide preliminary evidence that an enhanced protein regimen can benefit older males with prediabetes, especially with regard to physical function and body composition.This trial was registered at clinicaltrials.gov as NCT03835416.

Keywords: function; obesity intervention; older adults; prediabetes; protein

DOI: https://doi.org/10.1016/j.cdnut.2026.109460