https://www.mdpi.com/2218-273X/16/8/1218

Abstract

Skeletal muscle mitochondria possess the ability to autoregulate their health and functioning by the orchestration of mitochondrial quality control (MQC) pathways. This plasticity allows them to adapt to various stimuli, such as exercise. However, under pathological conditions, mitochondria can become dysfunctional, generating damage-associated molecular patterns (DAMPs), such as reactive oxygen species (ROS) and oxidized mitochondrial DNA (mtDNA). These DAMPs can launch an innate immune response, with consequences of widespread inflammation and atrophy. Integral to this is the NLRP3 inflammasome complex. Activation of the NLRP3 inflammasome results in maturation of caspase-1, which processes pro-inflammatory cytokines IL-1β and IL-18, as well as GSDMD. Consequently, the pore-forming GSDMD-N fragment induces pyroptosis, releasing mature IL-1β and IL-18. Exercise training is widely accepted as a potent mechanism to promote skeletal muscle health, particularly by remodeling the mitochondrial network and reducing the production of DAMPs. It has also been shown promote an anti-inflammatory milieu with the release of various myokines. Indeed, the potential of exercise to mitigate NLRP3 inflammasome-mediated inflammation and atrophy is promising. This review will examine the mechanisms underpinning inflammasome priming and activation, as well the effects of exercise, with an emphasis on the skeletal muscle.

https://www.ovid.com/jnls/acsm-msse/fulltext/10.1249/mss.0000000000004120~photobiomodulation-does-not-increase-mitochondrial

Abstract

Purpose:

Low-level laser therapy, also referred to as photobiomodulation (PBM), is rapidly gaining popularity as a non-invasive treatment for various conditions and as a means to enhance health and performance. PBM has been proposed to directly increase mitochondrial activity in skin and skeletal muscle and activate various molecular signalling pathways. However, evidence for the proposed properties of PBM in vivo in humans is lacking.

Methods:

In a within-participant study design, 12 healthy men and women (6/6 m/f; age: 25±6 y; BMI: 23.3±2.2kg/m2) received PBM on a randomized leg, while the other leg received sham-treatment (no light emitted, CON). Three cycles of PBM or sham-treatment were performed for 5 min 16 sec each (5.6 kJ light energy/cycle for PBM). Skin temperature was measured before and after treatment. After treatment, skin and muscle samples were collected from both legs. Mitochondrial respiration was measured in permeabilized muscle fibers and minced skin tissue using an Oroboros Oxygraph-O2k. Muscle metabolic gene expression was assessed using custom made microfluidic cards.

Results:

Skin temperature increased only in the PBM treated leg (+8.0±1.4 °C; P<0.001). No differences were observed between the PBM and CON treated legs in maximal complex I+II-linked respiration in skin (2.7±0.8 vs 2.6±0.7 pmol/sec/mg wet weight, respectively; P=0.66) or muscle (474±114 vs 467±81 pmol/sec/mg dry weight, respectively; P=0.71). Furthermore, no differences were observed in muscle mitochondrial ADP sensitivity (apparent ADP half-time: 1310±180 vs 1229±240 µM ADP, respectively; P=0.14). Of the 91 genes, expression between legs differed for 3 genes only.

Conclusions:

A single session of photobiomodulation does not increase mitochondrial respiration in skin or underlying muscle tissue and does not modulate muscle gene expression ex vivo in humans.

https://onlinelibrary.wiley.com/doi/10.1002/jcsm.70368

ABSTRACT

Background

Ultra-endurance sports are increasingly popular, yet the long-term physiological consequences of sustained extreme training loads remain poorly understood. In particular, the effects of prolonged ultra-endurance exercise on skeletal muscle structure, function and molecular remodelling are largely unknown. This case study examined a highly experienced ultra-endurance athlete who completed a world-record attempt to run 30 300 km, with extensive phenotyping focusing on skeletal muscle adaptations and recovery.

Methods

A 49-year-old male athlete (172 cm, 65 kg) ran ~70 km daily for 15 months. Musculoskeletal, cardiac and visceral ultrasonography, leg muscle strength and power measurements were performed before and after the challenge. Muscle biopsies (n = 4) from vastus lateralis were obtained immediately after completion and during 17 months of recovery to assess myosin heavy chain (MHC) composition, mitochondrial electron transport chain (ETC) complexes and proteins involved in mitochondrial turnover, autophagy and inflammation. Body composition, haematological and biochemical markers, and gut microbiota composition were monitored longitudinally.

Results

The athlete ran 30 300 km over 444 days, maintaining a daily distance of ~70 km despite substantial musculoskeletal discomfort, including a tibial stress reaction mid-challenge, which resolved gradually with continued running. Body mass decreased by ~3 kg, primarily reflecting fat loss (~83%), accompanied by reductions in muscle thickness, maximal strength and power. Circulating creatine kinase (3–15-fold), oxidative stress markers (~50%) and GDF8 (~10%–50%) were sustainedly increased, whereas IGF-I decreased (~10%–40%), suggesting a reduced anabolic environment during the challenge. Muscle biopsy analyses revealed a progressive recovery of mitochondrial function during the 17 months following the challenge, as evidenced by a progressive increase in ETC protein abundance and the expression of regulators of mitochondrial dynamics and quality control (MFN2, PARKIN, DRP1). In contrast, markers of autophagy, apoptosis and inflammation were decreased during the 17-months post-challenge (LC3A/B-I by ~50%, CASP3 by ~60% and NF-κBSer536 by ~20%). Muscle fibre composition showed extreme predominance of slow fibres (nearly 100% MHC-I), which persisted during recovery. Most molecular and functional alterations gradually resolved within 10–17 months. Gut microbiota diversity increased during the challenge, with enrichment of Bifidobacterium during running and Akkermansia during recovery.

Conclusions

Sustaining daily ultrarunning for more than 1 year induces substantial skeletal muscle remodelling, including reduced muscle size, impaired contractile function and mitochondrial maladaptations, despite largely preserved endocrine and haematological stability. These findings highlight skeletal muscle as a primary physiological system challenged during extreme endurance exercise and demonstrate that recovery from such perturbations may require more than one year.

Abstract

Skeletal muscle atrophy is a secondary complication in the aetiology of injury and chronic disease. Identifying mechanisms that control muscle mass is necessary to characterise atrophy and develop prevention strategies. We aimed to integrate transcriptomic and epigenomic data to identify key regulatory pathways controlled by promoter DNA methylation during muscle unloading. Twenty-one healthy men (20–40 years) completed a 4-week standardised exercise programme prior to a 14-day knee brace immobilisation with dietary control. Skeletal muscle mass and strength were assessed before and after immobilisation and biopsies were collected (m. vastus lateralis) before, at 3 days, and at completion at 14 days. RNA and DNA were isolated and analysed using Illumina RNA sequencing and DNA methylation 850K EPIC BeadChips. The 14-day immobilisation decreased muscle mass (∼9%; P < 0.0001) and strength (∼16%; P < 0.0001). At 3 days, most biological processes (BPs) were upregulated/hypomethylated (157 gene sets); upregulated BPs included cell signalling and protein ubiquitination and downregulated BPs included metabolism. After 14 days, BPs were predominantly downregulated/hypermethylated, including translation and ribosome biogenesis. Across both time points, HDAC4, GADD45A and CHRNA1 emerged as methylation-regulated candidate mediators of atrophy. HDAC4 and GADD45A showed strong correlations primarily at day 3, and CHRNA1 remained significant at both time points, extending prior observations in animals to human skeletal muscle. We have characterised changes in gene expression related to hypo- and hyper-methylation during muscle unloading in humans. These data extend our understanding of the regulatory processes that occur during skeletal muscle atrophy that, at the individual gene level, may be useful in developing strategies for reducing muscle wasting.

Highlights

• What is the central question of this study? What are the characteristics of global gene expression in skeletal muscle in response to limb immobilisation in young men?
• What is the main finding and its importance? Data obtained support the role of DNA methylation as a regulator of transcription and that methylation appears to impair gene expression for protein synthesis early and later amplify protein breakdown over 14 days of immobilisation. There are associations between methylation and transcription within biological processes as putative molecular targets to mitigate the debilitating impacts of muscle wasting.

Abstract

Patients with long COVID and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) suffer from post-exertional malaise. The accompanying physical inactivity may contribute to a lower aerobic capacity and may explain skeletal muscle adaptations in these patients. Here, we compare whole-body exercise responses and skeletal muscle adaptations after strict 60-day bed rest in healthy people with those in long COVID and ME/CFS patients, and healthy age- and sex-matched controls. Bed rest alters respiratory and cardiovascular responses to maximal exercise, which are dissimilar in patients. Bed rest causes muscle atrophy without altering fiber type. Both patient groups have more glycolytic fibers, and ME/CFS patients display type I-specific atrophy. Only after bed rest is oxidative phosphorylation capacity associated with maximal oxygen uptake. As skeletal muscle characteristics differ between patients and healthy individuals after bed rest, physical inactivity cannot solely explain the lower exercise capacity and skeletal muscle adaptations in long COVID and ME/CFS patients.

https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP291437

Abstract

Reductions in musculoskeletal mass and function can occur with ageing and disuse. While resistance exercise training is known to minimise these detriments, it is not always feasible. Vortex wave stimulation (VWS) may mitigate skeletal muscle decline in such scenarios. The aim of the present study was to explore the acute physiological and metabolic effects of VWS in healthy older adults. Fourteen participants consumed deuterium oxide (D2O) stable oral isotope tracer for 7 days. Serial skeletal muscle biopsies were obtained to measure integrated rates of myofibrillar (iMyoPS) and sarcoplasmic (iSarcPS) muscle protein synthesis and regulatory signalling over ∼48 h before (habitual) and after two consecutive-day bouts of VWS. Myoelectrical activity and muscle oxygenation during VWS, and pre-post changes in peripheral blood flow and concentrations of inflammatory and bone turnover markers were also measured. There was an increase in iMyoPS (0.23% day⁻¹, P = 0.025), but not iSarcPS (0.07% day⁻¹, P = 0.582) above habitual rates following VWS. There was no difference in the expression of anabolic signalling proteins, nor peripheral blood flow following VWS. Myoelectrical activity increased during VWS (9.47 µV, P = 0.010), while muscle oxygenation decreased at the gastrocnemius (P = 0.001) and quadriceps (P = 0.017). There was a reduction in P1NP (8.27 µg L⁻¹) and lactate (0.84 mmol L⁻¹) concentration post-VWS (both P < 0.001), while there was no difference in other biomarkers. This is the first study to demonstrate that VWS elicits acute physiological responses congruent with musculoskeletal adaptive remodelling, which warrants further exploration.

Key points

• Resistance exercise is known to mitigate skeletal muscle atrophy associated with ageing and/or disuse but is not always feasible.
• We investigated, for the first time, the effects of a novel mechanical stimulus – vortex wave stimulation (VWS) – on integrated rates of myofibrillar and sarcoplasmic muscle protein synthesis, alongside other musculoskeletal and physiological outcomes, in healthy older adults.
• We demonstrated that VWS elevated myofibrillar, but not sarcoplasmic muscle protein synthesis compared to baseline, while increasing myoelectrical activity and reducing muscle oxygen saturation, lactate and bone turnover markers.
• These findings suggest VWS elicits acute physiological responses congruent with musculoskeletal adaptive remodelling.

Abstract

Prolonged glucocorticoid exposure induces skeletal muscle atrophy through suppression of protein synthesis and activation of catabolic signalling pathways. Although exercise attenuates glucocorticoid-induced muscle loss, whether exercise-induced increases in body temperature contribute remains unclear. In this study, we examined whether exercise in different thermal conditions modulates skeletal muscle atrophy and intracellular signalling during glucocorticoid exposure. Female Sprague–Dawley rats (n = 48) were assigned to six groups: control (CON), dexamethasone-treated (DEX), cold exercise (∼5°C; CE), cold exercise with dexamethasone (CED), warm exercise (25°C; WE) and warm exercise with dexamethasone. Exercise protocols were matched, and dexamethasone was administered for 5 days. Dexamethasone reduced plantaris muscle mass (by 17%, P < 0.0001) and fibre cross-sectional area (27%, P < 0.0001). During dexamethasone treatment, exercise in a cold environment provided partial protection, with muscle mass higher than DEX (P = 0.0476), but both muscle mass and fibre CSA remained lower than CON (P = 0.0096 and P = 0.0215, respectively). In contrast, exercise in a warm environment preserved muscle mass and fibre CSA (no difference vs. CON) and resulted in higher muscle mass (P = 0.0070) and fibre CSA (P < 0.0001) than DEX. Exercise-induced increases in rectal temperature were associated with higher Hsp72 and Hsp25 expression, partial preservation of Akt–FoxO3a signalling and reduced MuRF1 expression, whereas exercise in a cold environment showed minimal heat shock protein response and limited suppression of catabolic signalling. These findings indicate that exercise-induced elevation of body temperature enhances protection against glucocorticoid-induced skeletal muscle atrophy and support a role for heat-associated cellular stress responses in modulating muscle protein turnover during glucocorticoid exposure.

Highlights

• What is the central question of this study? Does an exercise-induced increase in body temperature contribute to protection against dexamethasone-induced skeletal muscle atrophy, independent of exercise intensity?
• What is the main finding and its importance? Exercise attenuated dexamethasone-induced skeletal muscle atrophy in both cold (∼5°C) and warm (25°C) conditions; however, exercise performed in a warm environment, which elicited a greater rise in body temperature, resulted in superior preservation of muscle mass, accompanied by increased expression of heat shock proteins (Hsp72 and Hsp25), partial preservation of Akt–FoxO3a signalling and attenuation of MuRF1 upregulation. These findings identify exercise-induced elevation of body temperature as an important physiological modulator that augments the anti-atrophic effects of exercise during glucocorticoid treatment.

Abstract

Skeletal muscle displays remarkable plasticity, adapting its size and strength in response to mechanical loading, especially, from exercise. This process, known as hypertrophy, is fundamental to athletic training and rehabilitation, but is challenging to quantitatively predict due to its multifactorial, multiscale nature. Specifically, skeletal muscle hypertrophy results from an integration of macroscopic mechanical stimuli with the intracellular signaling pathways that govern muscle growth. In this work, we present a multiscale computational model that mechanistically integrates these mechanical and biochemical stimuli and offers a framework for predicting the outcomes of different types of exercise on skeletal muscle growth. The framework couples a transversely isotropic hyperelastic model for tissue-level mechanics with a system of ordinary differential equations representing the IGF1-AKT-mTOR-FOXO signaling pathway, a key regulator of protein synthesis and degradation. We link these scales using a volumetric growth model, where the signaling dynamics inform a growth tensor that drives changes in muscle cross-sectional area. This approach enables the simulation of long-term muscle adaptation, providing a mechanistic tool to investigate how different exercise protocols lead to macroscopic hypertrophy. Simulations from our model capture the temporal dynamics of hypertrophy under varying load protocols and highlight how feedback between protein synthesis and muscle growth regulates the dose-response relationship to prevent unbounded growth. Using muscle geometries derived from the Visible Human dataset, we study how human variations in muscle geometry affect hypertrophy. Finally, we demonstrate that the mechanochemical coupling between muscle geometry and signaling not only predicts macroscopic shape changes but also provides buffering from local signaling heterogeneity. Ultimately, this framework offers a predictive computational tool for optimizing training regimens and understanding the multiscale determinants of muscle adaptations.

Author summary

Skeletal muscle naturally adapts its size and strength in response to physical activity, a process that is essential for both athletic training and rehabilitation. However, predicting how a specific training routine will alter a muscle’s shape remains difficult. This is because muscle growth relies on a complex, multiscale chain of events, where physical forces from movements trigger chemical signals that slowly rebuild the tissue over time. To better understand this process, we developed a computational model that links these underlying cellular signals directly to the macroscopic physical changes in the muscle. When simulating different exercise routines in realistic human muscle geometries, we found that the complex internal fiber architecture of the muscle causes it to grow unevenly. We also observed that the physical continuity of the tissue acts as a mechanical buffer, helping to coordinate noisy, localized signaling into smooth overall growth. Ultimately, this framework provides a foundational first step towards understanding how and where muscle adds mass, laying the groundwork for more advanced predictive tools.

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.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://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://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.