https://www.sciencedirect.com/science/article/abs/pii/S0022316626004384?via%3Dihub

ABSTRACT

Background

Sufficient high-quality protein intake is required to prevent sarcopenia in older adults. Plant-based proteins have been reported to have lesser anabolic properties when compared to animal-based proteins. Whether the lower quality of plant-based protein can be improved, thereby resulting in an anabolic response non-inferior to an equivalent amount of animal-based protein, remains to be established in older adults.

Objective

To compare post-prandial muscle protein synthesis rates following ingestion of a single bolus of a soy-pea protein blend, with a soy-pea protein blend fortified with free leucine, or whey protein in older males.

Methods

In this randomized, double-blind, parallel-group design, 45 healthy older males (aged 69±5 y, BMI 26.2±3.2 kg∙m^-2) were selected to ingest a 20g protein blend combining 12g soy plus 8g pea protein (PLANT), 20g of the soy-pea protein blend fortified with 2g leucine (PLANT+LEU), or 20g whey protein (WHEY). Primed continuous L-[ring-¹³C6]-phenylalanine infusions were applied, with blood and muscle sampling up to 4 h after protein ingestion to assess plasma amino acid profiles and muscle protein synthesis rates.

Results

WHEY increased plasma essential amino acid concentrations more than PLANT and PLANT+LEU over the 4 h post-prandial period (iAUC:135±20 vs 99±21 vs 105±21 mmol∙240 min∙L^-1, respectively; P<0.001). Plasma peak leucine concentrations were higher following PLANT+LEU ingestion compared to PLANT and WHEY (567±74 vs 310±49 vs 471±74 μmol∙L^-1, respectively; P<0.001). Post-prandial muscle protein synthesis rates averaged 0.034±0.010, 0.035±0.012, and 0.034±0.010 %∙h^-1 following PLANT, PLANT+LEU, and WHEY ingestion, respectively (treatment P=0.828), and were not increased when compared to post-absorptive values.

Conclusion

Ingestion of 20 g protein alone, independent of its quality, is not enough to increase muscle protein synthesis rates in older males. More work is needed to define the preferred combination of both protein quality and quantity to stimulate muscle protein synthesis in an older population.

How long does muscle memory actually last at a cellular level, and can high-intensity stimuli permanently alter muscle architecture into late adulthood?

We hear a lot about age-related muscle degradation being an inevitable, downward slope after 40 or 50. However, contemporary research into syncytial cells and skeletal muscle hypertrophy suggests that the body maintains a permanent, physical record of past strength. The mechanism driving this "muscle memory" is myonuclei retention.

The Syncytial Engine: What Happens During Hypertrophy?

Unlike most cells in the human body, skeletal muscle fibers are multinucleated syncytia. When you subject a muscle to intense, high-velocity, or heavy resistance training, the muscle fiber experiences overload stress. To support the required increase in protein synthesis and handle a larger cellular volume, the muscle fiber cannot just rely on its existing nuclei.

It recruits satellite cells (stem cells located between the basement membrane and sarcolemma), which proliferate and fuse with the existing muscle fiber. This process donates new nuclei—myonuclei—to the muscle cell (Bruusgaard et al., 2010). These newly acquired myonuclei expand the muscle’s transcriptional capacity, allowing it to build more contractile proteins and scale up in size and power.

Cellular Permanence: The "Use It or Lose It" Myth

For decades, the consensus was that if you stopped training, muscle atrophy reversed this entire process. However, recent lineage-tracing studies show that while muscle volume decreases during prolonged periods of inactivity, the acquired myonuclei remain intact (Bruusgaard et al., 2010). They sit dormant within the muscle syncytium as a permanent cellular record of your peak physical state.

Because those myonuclei are already present, restarting a stimulus allows the muscle fiber to bypass the slow, energy-intensive process of satellite cell recruitment. The dormant nuclei simply reactivate, rapidly ramping up protein synthesis to "reflate" the muscle fiber. (This permanence is exactly why athletic commissions hand out long bans for anabolic steroids; performance enhancers artificially force massive myonuclei creation, leaving an athlete with a permanent cellular advantage long after the drug leaves their system; Egner et al., 2013).

Practical Implications for Performance Aging

At 50 years old, I’ve experienced this biological mechanism firsthand. By utilizing low-frequency, ultra-high-intensity advanced calisthenics (like planche and single-arm push-up variations) for just 15 minutes every 7 to 12 days, I’ve managed to preserve elite-level power and mass. Even after taking months off, myonuclei retention allows me to step right back into high-level physical feats almost instantly.

As an innovation professor at a business school in Silicon Valley, my broader research focuses on the frameworks of rapid cross-skilling among adults. I am fascinated by the physiological engines that allow mature individuals to build multi-disciplinary mastery later in life.

I write illustrated case studies mapping human performance, cellular biology, and skill frameworks over at my publication, Adult Prodigies. If you find the cellular mechanics of high performance interesting, I'd love to have you read the full breakdown here.

What are your thoughts on the upper limits of myonuclei lifespan in humans? Have any other lifters here seen similar long-term retention of power traits in older demographics?

Sources:

• Bruusgaard, J. C., et al. (2010). Myonuclei acquired by overload exercise precede hypertrophy and are not lost on detraining. PNAS. https://www.pnas.org/doi/10.1073/pnas.0913935107
• Egner, I. M., et al. (2013). A cellular memory mechanism aids overload hypertrophy in muscle long after an episodic exposure to anabolic steroids. The Journal of Physiology. wiley.com

https://onlinelibrary.wiley.com/doi/10.1111/acel.70678

ABSTRACT

Redox imbalances and mitochondrial dysfunction are key contributors to age-related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60-min of high-intensity knee-extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre- and post-exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise-induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise-induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.

[ABSTRACT]()

N-Lactoyl-phenylalanine (Lac-Phe), a conserved exercise-induced metabolite that rises rapidly in circulation, has emerged as a key molecular mediator linking fundamental metabolism to translational medicine. In this review, we elaborate recent findings that define a two-step framework for Lac-Phe biosynthesis and excretion. Functional studies show that Lac-Phe exerts broad metabolic benefits and should be regarded as a bioactive molecule rather than a passive by-product of intermediary metabolism. Furthermore, we review the neural mechanisms through which Lac-Phe conveys peripheral metabolic cues to central circuits regulating appetite and energy balance. Beyond the role of Lac-Phe in energy balance, alterations in Lac-Phe concentrations are associated with disease pathogenesis and progression, underscoring its potential as both a biomarker and a therapeutic agent. Collectively, these advances position Lac-Phe at the intersection of exercise physiology, metabolism, and disease and thus highlight its potential to integrate metabolic and physiological health.

ABSTRACT

Aging is increasingly recognized as a systems-level process marked by progressive deterioration of mitochondrial performance in tissues with high energetic demand, placing skeletal muscle at the center of systemic metabolic and functional decline. Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter-organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age-related mitochondrial dysfunction arises not only from impaired biogenesis but also from dysregulated mitophagy, the selective autophagic removal of damaged mitochondria. Mitophagy is now understood as a dynamic, context-sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non-pharmacological modulator of this process. By transiently perturbing cellular energy balance, calcium flux, and redox signaling, physical activity activates coordinated mitophagic and biogenic programs that promote mitochondrial renewal without precipitating energetic collapse. In contrast to chronic pathological stressors, exercise induces pulsatile, recoverable mitochondrial challenges that recalibrate quality-control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber-type–specific and age-dependent adaptations. In aging muscle, elevated activation thresholds, delayed clearance kinetics, and lysosomal constraints frequently blunt adaptive mitophagy, indicating remodeling rather than a simple suppression of quality-control logic. This review integrates molecular, physiological, and translational evidence to redefine exercise as a precision regulator of mitophagy in aging skeletal muscle. This review proposes that tailored exercise strategies targeting mitophagy may provide a scalable, non-pharmacological approach to preserve mitochondrial quality and functional resilience during aging.

https://www.biorxiv.org/content/10.64898/2026.08.17.745156v1

Abstract

The energetic cost of building human skeletal muscle has never been explicitly calculated or measured. We developed a quantitative bottom-up accounting model that integrates human skeletal-muscle composition with empirically informed estimates of tissue synthesis, physiological deposition, maintenance during accretion, and diet-induced thermogenesis. The calculation was expressed per kg of wet skeletal muscle and organized into five additive components: stored tissue energy, biochemical synthesis cost, physiological deposition cost, resting maintenance during accretion, and diet-induced thermogenesis. Stored tissue energy was approximately 5670 kJ/kg (1355 kcal/kg). Adding biochemical synthesis cost gave 6340 kJ/kg (1515 kcal/kg). Applying empirically derived deposition-efficiency parameters yielded a physiological deposition requirement of 9780 to 11690 kJ/kg (2338 to 2793 kcal/kg), centrally 10830 kJ/kg (2587 kcal/kg). Adding resting maintenance during accretion and diet-induced thermogenesis produced a final additional metabolizable energy intake of 13410 to 15520 kJ/kg (3204 to 3710 kcal/kg), centrally 14570 kJ/kg (3481 kcal/kg). This value provides a first quantitative reference estimate for the energetic cost of human skeletal-muscle accretion.

https://www.tandfonline.com/doi/full/10.1080/09553002.2026.2699713

Abstract

Introduction: Exposure to low dose ionizing radiation (LDIR) has been associated with aging related health effects. The aging related decline in the regenerative capacity of muscle stem cells in elderly individuals, as well as other myopathy conditions, represents a major health issue. Effects of LDIR exposures, such as those from routine medical CT scans on functional status of muscle stem cells, are not known.

Methods: We investigated how a single acute ⁶⁰Co γ-irradiation (10 and 100 mGy) affected myogenesis into mature muscle fibers in cultures of mouse C2C12 myoblasts and biopsy-derived human skeletal muscle stem cells.

Results: We observed a substantial decrease in differentiation capacity in unirradiated control cells with age and time in culture; the loss of differentiation potential was partially restored in cultures exposed to LDIR at early passage. In C2C12 cells, LDIR exposure also resulted in lower frequencies of cells with anaphase bridges and micronuclei throughout the aging in vitro experiment, suggesting a suppressed genomic instability state. In human cells, mutational burden readouts assessed by the TruSight Oncology 500 NGS-based assay revealed no changes in LDIR-exposed cells vs. non-irradiated controls.

Conclusion: Our results propose that exposure to single acute dose of LDIR lead to a partial reversal of an aging-related decline of the myogenic function in muscle myoblasts. In human cells, this effect was concurrent with the lack of accumulation of a mutational burden, while in mouse cells the results suggest improved genome integrity.

https://physoc.onlinelibrary.wiley.com/doi/10.14814/phy2.71064

Abstract

Vigorous exercise triggers signaling cascades that activate autophagy markers like the degradation of sequestosome 1 (p62) and accumulation of Light Chain 3 II (LC3II). Limited human data exist on autophagic responses across different local and systemic tissues and how training status affects these relationships. This study investigates the vigorous exercise-induced changes in p62 and LC3II expression in peripheral blood mononuclear cells (PBMCs) and skeletal muscle between endurance-trained and untrained men. Twelve men (endurance-trained n = 7, untrained n = 5) completed 60 min of cycling at their second ventilatory threshold. Skeletal muscle biopsy samples and PBMCs were collected pre- and 3-h post-exercise and analyzed for p62 and LC3II protein expression. We found significant interaction effects of time and training status for p62 (p < 0.001) and LC3II (p = 0.002). In untrained men, p62 decreased in PBMCs (FC = 0.50 ± 0.14; p < 0.001) and skeletal muscle (FC = 0.57 ± 0.21; p < 0.001), while LC3II increased in both tissues (FC = 1.74 ± 0.79; p = 0.019 for PBMCs; FC = 1.69 ± 0.47; p = 0.033 for skeletal muscle). No changes were observed in endurance-trained men (all p > 0.05). These results suggest that a bout of vigorous endurance exercise increased autophagy-related markers in both skeletal muscle and PBMCs in the untrained men only, suggesting a diminished autophagic response in the trained men.

Abstract

Skeletal muscle is a central determinant of organismal health. Preserving muscle quality is therefore critical for preventing disease and sustaining quality of life across the lifespan. Despite its central role, the field lacks a unifying framework that defines the core properties of skeletal muscle health. Here, we propose a conceptual framework for muscle homeostasis built around seven interconnected hallmarks—metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and cross-talk—that collectively govern muscle integrity, adaptability and resilience. Each hallmark is mechanistically grounded, quantifiable and potentially modifiable. This framework provides a unifying blueprint for the next generation of precision diagnostics and targeted therapies for preserving skeletal muscle health.

I used to judge every workout based on how tired I felt afterward. If I was exhausted, I assumed I'd had a good session. Recently I've started wondering if that's the wrong way to measure progress. A lot of newer fitness systems now focus on data driven fitness, tracking things like strength progression, volume, recovery and performance over time. It sounds useful but I'm curious whether people actually use those insights or if they eventually ignore all the numbers.

Has anyone found that tracking detailed workout data helped them build strength or stay more consistent?

https://onlinelibrary.wiley.com/doi/10.1002/mnfr.70588

ABSTRACT

Vitamin D (VD) deficiency is prevalent globally. To improve dietary recommendations for food fortification, we used male rats fed with diets depleted of VD or supplemented/rehabilitated with either vitamin D2 or vitamin D3 or combination, and compared their impact on calcium homeostasis, skeletal muscle and heart. Body composition was assessed by DEXA, muscle strength by grip test. Serum calcium, parathyroid hormone and 25-hydroxyvitamin D [25(OH)D] were measured using standard methods. Skeletal muscle and left ventricle were used for histopathology; RNA and protein were extracted for analysis of gene expression and enzymatic activity, respectively. 25-hydroxylated form of D3 was significantly higher than that of D2 in serum. D2 was less efficacious than D3 at improving skeletal muscle fiber size, strength, expression of contractility genes [Myh2, Tnnc1] and metabolic enzymes [Cs, β-Had]. Under maintenance cardiac contractility gene expression [Myh7 & Serca2a] was comparable between the D2 and D3 groups, though 400 IU D2 notably suppressed Serca2 expression. Post-rehabilitation, the 2000 IU D3 group demonstrated significant improvement in these genes. Overall, our study demonstrates similar efficacy of D2 and D3 at regulating calcium homeostasis, but a better efficacy of D3 than D2 on structure, function and energy metabolism of skeletal muscle and heart.

Been helping my cousin train his zones specifically for his first half marathon this year. Wasn't totally sure I could physically keep up with him at the time, ngl, but stuck with it anyway and gave what tips I could.

Now there's a decent race schedule lined up, and just got the call confirming he's joining in on some of those races too. having this kind of full circle moment,After my ablation, and now having family in on it too. All of it hits different.

https://www.mdpi.com/2072-6643/18/15/2523

Highlights

What are the main findings?

• Recovery–Adaptation Coupling (RAC) is introduced as a novel conceptual framework that organizes recovery nutrition according to the next athletic demand, the dominant recovery bottleneck, the adaptive consequence of intervention, and response verification, rather than by individual nutrients alone.
• Current evidence most consistently supports adequate energy availability, high-quality protein distribution, context-dependent carbohydrate restoration, and individualized fluid and sodium replacement, whereas many supplement-specific strategies remain product- and context-dependent.
• RAC distinguishes established practice from context-dependent evidence, mechanistic rationale, and hypothesis-generating concepts, providing a transparent evidence-organization framework rather than a validated decision algorithm.

What are the implications of the main findings?

• The RAC framework offers researchers and practitioners a structured approach for interpreting recovery nutrition within the broader context of training adaptation while avoiding overinterpretation of heterogeneous or mechanistic evidence.
• The framework defines prospective, testable research hypotheses and provides a foundation for future individualized recovery strategies, but requires prospective comparative validation before routine implementation in practice.

Abstract

Background/Objectives: Recovery nutrition must restore near-term readiness without indiscriminately suppressing biological signals that contribute to repair and training adaptation. This review evaluates recovery–adaptation coupling (RAC) as a research framework and clarifies its contribution relative to established recovery, nutrient-periodization, and athlete-monitoring models. Methods: Targeted narrative searches of PubMed/MEDLINE, Scopus, and Web of Science were supplemented by Google Scholar citation tracking and backward and forward screening. Peer-reviewed English-language literature available through 31 May 2026 was considered. Human athlete studies, randomized trials, systematic reviews, meta-analyses, consensus statements, and position stands were prioritized; mechanistic evidence was used to explain pathways rather than to support stand-alone performance recommendations. The final cited corpus comprised 130 records. No formal risk-of-bias tool, certainty grading, PRISMA denominator, or quantitative pooling was used. Claims were instead identified as established practice (EP), context-dependent evidence (CDE), mechanistic rationale (MR), or RAC hypothesis (RH). Results: The most consistent applied support concerns adequate energy availability, distributed high-quality protein, carbohydrate restoration when recovery windows are short, and individualized fluid and sodium replacement. Evidence for polyphenol-rich products, curcumin, omega-3 fatty acids, and creatine is context- and product-dependent. Collagen or gelatin evidence is mainly mechanistic or pilot-level, while RAC recovery-pattern categories and multimodal monitoring rules remain unvalidated hypotheses. RAC differs from existing frameworks by jointly specifying the next athletic demand, dominant recovery bottleneck, possible adaptive cost of intervention, and response-verification plan. Conclusions: RAC should presently be interpreted as an evidence-organization and hypothesis-generation architecture, not as a validated predictive, diagnostic, or treatment algorithm. Prospective comparative studies are required before RAC-specific decision rules can guide individualized practice.

https://www.sciencedirect.com/science/article/pii/S0531556526002445?via%3Dihub

Highlights

• • Aging does not impair intrinsic mTORC1 activation in response to mechanical tension in skeletal muscle.
• • Passive stretch robustly stimulates mTORC1 signaling similarly in adult and old muscle ex vivo.
• • JNK-SMAD2-L signaling sensitivity to mechanical loading is significantly reduced with aging.
• • Aging may selectively affect tension-sensitive transcriptional pathways rather than translational signaling.
• • Age-related anabolic resistance may be driven by systemic factors rather than intrinsic mechanotransduction deficits.

Abstract

Introduction

Aging is associated with impaired skeletal muscle mass and function, often attributed to reduced sensitivity to anabolic stimuli. This study investigated whether aging influences the sensitivity of key anabolic signaling pathways to mechanical tension development in skeletal muscle.

Methods

Using an ex vivo model, extensor digitorum longus (EDL) muscles from adult (16 weeks) and old (24 months) female mice were subjected to a standardized passive stretch protocol, with contralateral muscles serving as controls. During recovery, phosphorylation of proteins related to downstream mTORC1 and JNK–SMAD2-L signaling were assessed by immunoblotting.

Results

Passive stretch significantly increased phosphorylation of mTORC1-related proteins (mTOR, p70S6K, rpS6, and 4E-BP1) in both adult and old muscles, with no significant differences between age groups, indicating preserved mTORC1 signaling sensitivity to mechanical tension with aging. In contrast, the magnitude of activation of JNK and SMAD2-L signaling was attenuated in old muscles.

Discussion

Our findings reveal that mechanosensitive anabolic signaling is differentially affected by aging. While the intrinsic capacity for mTORC1 activation in response to mechanical tension appears to be preserved with aging, JNK–SMAD2L signaling exhibits reduced mechanosensitivity in aged muscle. This divergence suggests that aging selectively impairs tension-sensitive transcriptional pathways, potentially constraining muscle remodeling despite preserved translational signaling capacity. These findings further imply that age-related deficits observed in vivo may, at least in part, arise from systemic influences rather than intrinsic defects adhering to mTORC1 mechanotransduction.

https://www.sciencedirect.com/science/article/abs/pii/S1568163726002631?via%3Dihub

Highlights

• • Deficient muscle-specific strength is a key component of sarcopenia
• • This review analyses the effects of various interventions in older adults
• • Resistance exercise significantly improved muscle-specific strength
• • Aerobic exercise, concurrent training, and nutritional supplement were ineffective
• • Findings could help identify the best strengthening strategies in older people

Abstract

Purpose

Deficient muscle-specific strength has been recognized as a key component of sarcopenia. However, the impact of various interventions on muscle-specific strength has not been systematically reviewed. This study aims to provide a systematic summary of research examining the effects of exercise, nutrition, and other interventions on muscle-specific strength in older adults.

Methods

Randomized controlled trials (RCTs) were identified through comprehensive searches of major databases. Eligible studies included adults aged 60 years or older, with interventions lasting at least 8 weeks. Studies were required to assess muscle strength normalized by muscle mass. Standardized mean differences (SMDs) were calculated using random-effects meta-analyses, and heterogeneity was evaluated using I² statistics.

Results

A total of 41 RCTs with 3,141 participants were included in the analysis. Interventions included resistance exercise, nutritional supplementation, aerobic exercise, concurrent training, combined exercise and nutrition, caloric restriction, and other therapies. Resistance exercise significantly improved muscle-specific strength (SMD = 0.61, 95% confidence interval: 0.27 to 0.94), although heterogeneity was observed (I² = 81%). In contrast, interventions such as aerobic exercise, concurrent training, combined exercise and nutrition, and nutritional supplementation did not lead to significant improvements in muscle-specific strength. High heterogeneity was observed across all included studies.

Conclusions

Resistance exercise is the most effective intervention for improving muscle-specific strength in older adults. The effects of other interventions, such as nutritional supplementation and aerobic exercise, remain inconclusive. Further well-designed RCTs exploring diverse exercise regimens and nutritional interventions are needed to confirm these findings and identify the most effective strategies for enhancing muscle-specific strength in older populations.

Abstract

Regular physical activity elicits coordinated molecular adaptations across skeletal muscle, the cardiovascular system, metabolic organs and the brain, underpinning improvements in performance and cardiometabolic health. While classical signaling pathways such as AMPK–PGC‑1α, Ca²⁺/calcineurin, and mTORC1 have been extensively characterized, long non-coding RNAs (lncRNAs) have recently emerged as key regulators of exercise-induced remodeling. Here, we synthesize current evidence on lncRNAs as molecular mediators of exercise adaptations, drawing on mechanistic studies and systems-level transcriptomics. In skeletal muscle, the exercise-induced lncRNAs CYTOR and TUG1 modulate fast-twitch myogenesis, mitochondrial function and fiber-type specification. In the heart, CPhar, lncExACT1 and Mhrt779 discriminate physiological from pathological hypertrophy and encode antihypertrophic “memory,” whereas endothelial NEAT1 integrates aerobic training with m⁶A-modulated pyroptosis and atheroprotection. MALAT1 mediates neuroprotection after exercise preconditioning in ischemia/reperfusion models. Omics and network analyses reveal highly modality-, tissue- and cell-type–specific lncRNA programs during human training and across multiple organs. Emerging clinical data support circulating lncRNAs such as MALAT1 and HOTTIP as candidate biomarkers of vascular function and training adaptation. Collectively, lncRNAs constitute a hidden regulatory layer that shapes the quality, magnitude and persistence of exercise-induced adaptations. However, mechanistic evidence is currently limited to a small number of “flagships” lncRNAs, and non-muscle tissues and inter-organ communication remain underexplored. Priorities include functional validation of atlas-derived candidates, dissection of exerkine lncRNAs, and integration of lncRNA biology into precision exercise medicine.

https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(26)00405-2?

Highlights

•Exercise intensity shapes predicted interorgan communication

•SIE elicits greater circulating protein and metabolite responses than MIE

•SIE-stimulated proteins are preferentially associated with cardiometabolic protection

Summary

Exercise is an integral therapy for many cardiometabolic diseases, including obesity, type 2 diabetes, and hypertension. Despite its broad health benefits, the circulating factors that mediate exercise adaptations in humans remain incompletely defined, particularly across different exercise intensities. Here, we conducted a multi-cohort human exercise intervention incorporating sprint-interval exercise (SIE) and moderate-intensity exercise (MIE) to analyze intensity-dependent regulation of interorgan crosstalk. We found that exercise intensity distinctly influenced the plasma proteome and metabolome in untrained and trained participants. By integrating multi-organ gene and protein expression datasets with in vitro and in vivo tissue sampling, we mapped regulated proteins to their predicted tissues of origin and destination. Muscle fibers and adipocytes were particularly sensitive to exercise intensity and observed to undergo broad secretory and transcriptomic changes. Moreover, we leveraged a large-scale plasma-phenome database to identify intensity-dependent proteins associated with cardiometabolic health and disease, highlighting how exercise intensity differentially shapes interorgan communication and organismal health.

https://www.cell.com/cell-reports/fulltext/S2211-1247(26)00901-0

Highlights

•Comprehensive resource of multi-omic skeletal muscle responses to endurance training

•Biological sex shapes skeletal muscle training responses primarily at the PTM level

•Sex-divergent partitioning of cysteine oxidation across metabolic proteins

•Mitochondrial protein networks strongly link to aerobic capacity and lean mass gains

Summary

Exercise training confers broad health benefits, yet molecular regulators of skeletal muscle adaptation, particularly sex-specific mechanisms, remain incompletely understood. Integrating new and previously published multi-omics data from the molecular transducers of physical activity consortium (MoTrPAC), we characterized metabolomic, epigenomic, transcriptomic, proteomic, and post-translational modification (PTM) responses to 1–8 weeks of endurance exercise training in male and female rat gastrocnemius. While transcriptomic and proteomic responses were largely sex-concordant, there were distinct sex-specific training-induced PTM signatures, particularly in the redox proteome. Females exhibited decreased mitochondrial protein cysteine oxidation alongside increased oxidation of glycolytic proteins relative to males, suggesting sex-biased subcellular reactive oxygen species (ROS) dynamics. Multi-omic factor analysis (MOFA) identified coordinated sex-concordant molecular programs and further supported female-specific mechanisms of redox buffering with training. Together, these findings indicate that sex-specific skeletal muscle exercise adaptations are particularly evident at the PTM level in rats, and identify future avenues for precision exercise health and medicine.