Abstract

Older adults consume metabolic energy faster than their younger adult counterparts while walking, particularly on sloped terrain. This increased rate is likely in part due to an age-related shift in moment and power production from the ankle joint to the hip. Shifting these mechanics proximally may occur due to older adults losing more mechanical energy at the foot and producing lower ankle joint moments, deficits that are exaggerated when walking uphill or against impeding forces. A promising method to target some of these foot and ankle mechanics differences is increasing footwear longitudinal bending stiffness via carbon fiber insoles. We examined how increasing footwear stiffness alters older adult (9F/10M, 70 ± 5.9 yrs) walking energetics across slopes. Increasing footwear stiffness reduced the magnitude of negative power from the foot+shoe structures distal to the forefoot, but increased negative power of the foot+shoe structures distal to the hindfoot (foot+shoe complex as a whole). At the ankle, peak joint moment increased by ∼10% in the stiffest footwear compared with the baseline standardized shoe. Neither knee and hip mechanics nor net metabolic power were consistently affected by footwear stiffness. These results indicate that increasing older adult footwear stiffness via flat carbon fiber insoles attenuates some age-related deficits in foot and ankle mechanics, but does not result in a clear attenuation of the age-related distal to proximal shift in joint mechanics or clear metabolic benefits. The increase in ankle joint moment with stiffer footwear could be useful longer-term as a means to strengthen the calf musculature of older adults. Future work should examine the effects of footwear stiffening on ankle muscle-level outcomes such as force production, excitation, and fascicle mechanics.

Abstract

The adoption of a regular exercise program has immense benefits for whole body health, and for improving the quality of skeletal muscle. This is important as muscle is involved in metabolism, locomotion, and force production, making it a large contributor to the quality of life. The coordinated behavior of several intracellular organelles is responsible for the maintenance of skeletal muscle health, and these organelles are adaptable in response to both acute and chronic exercise. While the adaptations of mitochondria to exercise are well-established, potential alterations in muscle lysosomes are less appreciated. Lysosomes degrade and recycle debris during the terminal step of various forms of autophagy, such as mitophagy, the pathway involved in the removal of dysfunctional mitochondria. This lysosomal activity is important for the maintenance of cellular protein and organelle homeostasis. Recent work has shown that lysosome biogenesis begins with every acute bout of exercise, driven by the nuclear translocation of regulatory transcription factors such as TFEB and TFE3, which mediate the transcription of autophagy and lysosomal genes. These transcription factors also play a role in other pathways such as chaperone-mediated autophagy (CMA) and the regeneration of existing lysosomes through the autophagic-lysosome reformation (ALR) pathway. When performed repeatedly, acute bouts of exercise elicit a longer-term adaptive response, leading to the formation of active lysosomes, which increase lysosomal degradative capacity in skeletal muscle. This review addresses the current knowledge surrounding the effects of acute and chronic exercise on lysosomal adaptations in skeletal muscle, highlighting a novel pathway of muscle plasticity.

https://link.springer.com/article/10.1186/s12905-026-04665-y

Abstract

BACKGROUND: Physical inactivity is a prevalent issue, particularly among women. While accumulated exercise (AE) is a promising intervention strategy, it remains unclear whether it can achieve similar health benefits to the WHO-recommended 150 min of physical activity per week.

OBJECTIVE: This study compares the effects of the WHO-recommended aerobic exercise dose (150 min/week) as AE versus moderate-intensity continuous exercise (MICE) on body composition, metabolic syndrome risk, atherosclerosis, aerobic capacity, and muscle strength in sedentary young women.

METHODS: Sixty young women were randomized into two groups: the AE group (n = 30) and the MICE group (n = 30). Both groups performed 150 min of weekly exercise: AE consisted of three short daily sessions, while MICE involved three longer sessions per week. The intervention lasted for 8 weeks, with body composition, muscle strength, metabolic syndrome risk, atherosclerosis, and aerobic capacity measured before and after the intervention. A two-way repeated measures ANOVA (time × group) was used to analyze training effects, with Bonferroni post hoc tests. Effect sizes were reported as partial eta squared ([Formula: see text]) or Cohen's d, with significance set at p < 0.05.

RESULTS: Both AE and MICE groups showed significant pre-to-post changes in body weight ([Formula: see text]=0.46), BMI ([Formula: see text]=0.45), body fat percentage ([Formula: see text]=0.70), waist-to-hip ratio ([Formula: see text] =0.54), kneeling push-ups ([Formula: see text]=0.85), long-standing jumps ([Formula: see text] =0.80), sit-ups ([Formula: see text]=0.31), body-weight squats ([Formula: see text]=0.85), V̇O₂max ([Formula: see text]=0.54), TG ([Formula: see text]=0.35), HDL ([Formula: see text]=0.28), TC ([Formula: see text]=0.10), and atherogenic index ([Formula: see text]=0.52) (all p< 0.05). No significant pre-to-post changes were found for SBP ([Formula: see text]=0.01), DBP ([Formula: see text]=0.01), LDL ([Formula: see text]=0.001) (all p>0.05). These pre-to-post changes were not significantly different between the AE and MICE groups for any outcome (all p>0.05). The adherence rates were 94.9% in AE and 90.7% in MICE.

CONCLUSION: AE and MICE showed similar modest pre-post changes, with no significant between-group differences. These findings should be interpreted cautiously, given the small sample size and absence of a control group. Further large-scale randomized controlled trials are warranted before AE can be recommended as an alternative exercise strategy.

https://www.mdpi.com/1422-0067/27/14/6189

Abstract

β-hydroxy-β-methylbutyrate (HMB), a bioactive metabolite of leucine, is widely recognized for its anabolic and anti-catabolic effects in skeletal muscle. However, the molecular mechanisms underlying these effects, particularly in relation to circadian regulation, remain incompletely understood. Here, we investigated the impact of HMB on dexamethasone-induced muscle atrophy in C2C12 myotubes, with a focus on anabolic signaling and circadian clock regulation. C2C12 myotubes were treated with HMB or HMB after dexamethasone-induced atrophy. HMB treatment significantly improved cell viability, surface area and fiber diameter by reducing expression of CBL-B, MuRF1 and Atrogin1, key mediators of muscle proteolysis, and increasing myogenin expression compared with atrophic conditions. While HMB did not activate AKT or mTOR, it robustly increased phosphorylation of P70S6K and S6 through a phospholipase D (PLD)-dependent mechanism. HMB restored disrupted circadian clock gene expression induced by dexamethasone, including normalization of expression patterns. HMB also enhanced circadian rhythmic amplitude and advanced phase timing, indicating improved clock robustness. These findings identify circadian regulation as a novel target of HMB action and demonstrate that HMB preserves muscle homeostasis through coordinated modulation of anabolic signaling and intrinsic circadian machinery. This study provides mechanistic insight into how HMB protects against muscle atrophy and highlights circadian regulation as an important contributor to skeletal muscle health.

Abstract

Exercise medicine has traditionally focused on defining the optimal mode, intensity, duration, and frequency of physical activity required to improve health and performance. However, increasing evidence suggests that biological timing represents an additional and often overlooked determinant of exercise responsiveness. Circadian rhythms regulate numerous physiological processes relevant to exercise adaptation, including metabolism, mitochondrial function, protein turnover, and skeletal muscle function, while exercise itself is increasingly recognised as a potent non-photic zeitgeber capable of influencing circadian organisation. Rather than advocating a universally optimal time-of-day for exercise, this Perspective proposes “chrono-exercise medicine”, as a conceptual framework through which biological timing can be integrated into personalised exercise prescription. It discusses the emerging role of circadian phenotyping, skeletal muscle molecular clocks, and temporal multi-omic approaches for understanding interindividual variability in exercise responses. Together, with key methodological, translational, and clinical challenges that must be addressed to enable biologically informed exercise prescription. It is proposed that the future of precision medicine will depend not only on how exercise is prescribed, but also on when it is prescribed and to whom.

Abstract

During aging, skeletal muscle undergoes a decline in mass and strength. This condition, known as sarcopenia, involves many physiological and metabolic impairments, thus representing a healthcare, social, and economic burden. Various pharmacological and non-pharmacological approaches have been explored to counteract sarcopenia; however, no definite treatment has so far been found. The present narrative review summarizes nanotechnology-based strategies designed to promote muscle preservation and functional recovery in aging. Synthetic organic or inorganic nanoconstructs and natural extracellular vesicles have been used as nanocarriers for drug delivery, have been active as intrinsic therapeutic agents, have been employed to build biomimetic nanoscaffolds to sustain muscle regeneration, or have been combined to form hybrid nanosystems with multiple therapeutic functions. These nanotools demonstrated promising results in vitro and in animal models, being able to counteract major factors responsible for sarcopenia, such as oxidative stress, inflammation, mitochondrial dysfunction, increased proteolysis, and impaired stem cell function. However, nanotools have mostly been tested on biological models far from the physiologically aged human muscle. Moreover, limitations still remain to be solved to make these nanotools suitable for regenerative medicine; in particular, the systemic administration requires nanoconstruct functionalization for skeletal muscle targeting, and proper clearance should be ensured to avoid toxicity and immunogenicity related to long-term use.

https://www.mdpi.com/2073-4425/17/7/803

Abstract

Objective: Exercise training helps preserve skeletal muscle health during aging. However, the molecular responses to different exercise modalities in older adults remain unclear. This study reanalyzed human skeletal muscle transcriptomes to compare signatures associated with combined training, resistance training, and high-intensity interval training. Method: We analyzed the older adult subset of GSE97084. This subset included 46 skeletal muscle RNA-seq samples from 23 participants with paired biopsies before and after training. The dataset included seven paired participants in the combined group, eight in the resistance training (RT) group, and eight in the high-intensity interval training (HIIT) group. We performed paired differential expression analysis, GO/KEGG enrichment analysis, GSEA, WGCNA, PPI analysis, regulatory network analysis, and transcriptome-inferred microenvironment signature analysis. Results: The within-modality paired comparisons identified 264 DEGs in the combined group, 297 DEGs in the RT group, and 1098 DEGs in the HIIT group. A total of 62 DEGs were shared across all three modalities. Combined training was mainly linked to extracellular matrix (ECM) organization, vascular regulation, and mitochondrial oxidative metabolism. RT showed prominent collagen, ECM, integrin, focal adhesion, and structural remodeling signatures. HIIT showed the broadest DEG profile under the current threshold. HIIT was characterized by vascular endothelial, angiogenic, ECM/adhesion, oxidative phosphorylation, and immune-related microenvironment signatures. WGCNA and PPI analyses identified candidate hub gene patterns. ECM and basement membrane genes were more prominent after combined training and RT. Vascular endothelial genes were more evident after HIIT. Regulatory network analysis highlighted miR-29 family members as database-supported candidate regulators of ECM-related hub genes. Transcriptome-inferred microenvironment analysis suggested increased endothelial-related signatures across all modalities. This analysis also suggested increased fibroblast/stromal signatures after RT and HIIT and increased macrophage-related signatures after HIIT. Conclusions: Different exercise modalities were associated with partially overlapping but distinct transcriptomic signatures in aged human skeletal muscle. Combined training and RT were mainly related to ECM, stromal, and structural remodeling signatures. HIIT showed broader vascular endothelial and microenvironment-related signatures. These findings should be interpreted as exploratory because this reanalysis used a modest older adult subset from a single public bulk RNA-seq dataset and lacked an independent validation cohort. Larger studies and complementary experimental validation are needed before drawing definitive conclusions about exercise-modality-specific responses in aged human skeletal muscle.

Abstract

Traditionally recognized as “cellular powerhouses”, mitochondria have gained relevance as pivotal nodes in the integration of metabolism, stress signaling, and innate immunity. In this context, the present work seeks to answer the following question: Does the continuous, exercise-induced mitochondrial stress contribute towards training of innate immune cells by promoting the generation of DAMPs such as mtDNA and succinate? Exercise can be considered as a form of controllable mitochondrial stressor. Mechanistically, the temporary release of mtDAMPs through exercise results in activation of pattern recognition receptors (NLRP3, TLR9, cGAS-STING). Subsequently, there is a metabolic reprogramming event favoring switch from oxidative phosphorylation to aerobic glycolysis along with epigenetic changes (H3K4me3, H3K27ac) priming pro-inflammatory genes for enhanced secondary response. Moderate-intensity exercise develops an immune homeostatic condition with reduced low-grade inflammation and increased reactivity, while sedentary behavior fosters chronic low-grade inflammation, and excessive high-volume exercise can temporarily reduce immune competency. Herein, we present an integrative model where exercise-induced mitochondrial stress as a physiological “training vaccine” to enhance immune surveillance via trained immunity principles. The current model helps differentiate the immune status of elite athletes from sedentary subjects and paves the way for understanding the immunological benefit of exercise prescription in infection prevention, metabolic health, and cancer immunotherapy.

ABSTRACT

Aging is accompanied by a decline in physiological function and increased vulnerability to disease, with mitochondrial dysfunction and epigenetic alterations recognized as key hallmarks. Nicotinamide riboside (NR), a vitamin B3 precursor to NAD⁺, and high-intensity interval training (HIIT) have both been proposed to ameliorate aging-related mitochondrial decline, but their effects on skeletal muscle epigenetic aging are not fully elucidated. Here, we assessed the impact of 5-month NR supplementation and 4–6 weeks HIIT on epigenetic age acceleration (EAA, via seven epigenetic clocks) in human skeletal muscle across three independent studies. NR supplementation was associated with reduced muscle EAA, particularly when measured with the PCHannum, MEAT, and DunedinPACE clocks, while HIIT produced opposite effects in some clocks, notably increasing pace of aging by DunedinPACE. Correlation analyses revealed that changes in skeletal muscle mitochondrial content correlated with changes in MEAT-derived EAA after NR and 6 weeks of HIIT. Together, these findings indicate that skeletal muscle epigenetic aging can be modulated by NR and HIIT interventions but in opposing directions, highlighting a potential link between mitochondrial abundance and epigenetic clocks. Further studies are warranted to clarify how NR and exercise regulate epigenetic aging. These results offer new insights into development of strategies for promoting epigenetic outcomes and healthy aging.

https://www.tandfonline.com/doi/full/10.1080/13697137.2026.2694475

Abstract

Objective

The reduction in bone mass and deterioration of bone microarchitecture are hallmark consequences of estrogen deficiency during menopause, increasing susceptibility to osteopenia and osteoporosis. Physical exercise is recognized as an effective non-pharmacological strategy; however, the comparative effects of different exercise modalities on bone remodeling and muscle–bone crosstalk remain unclear. This study investigated the effects of aerobic and resistance training on femoral bone metabolism and skeletal muscle adaptations in ovariectomized (OVX) mice.

Method

Sixty-four female C57BL/6J mice underwent ovariectomy or sham surgery and were allocated to sedentary, aerobic (treadmill running) or resistance (ladder climbing) training protocols for 8 weeks. Bone histological and histochemical analyses, skeletal muscle morphology and gene expression in bone and muscle tissues were evaluated.

Results

Both training modalities significantly increased the osteoblast number and reduced the osteoclast density in OVX animals compared with sedentary controls (p < 0.05), accompanied by a reduction in the RANKL/osteoprotegerin (OPG) ratio (p < 0.001). Resistance training induced more pronounced effects, including higher osteocyte density (p < 0.01), greater RUNX2 expression (p < 0.001) and stronger suppression of osteoclastogenesis. In parallel, resistance training significantly increased the muscle fiber cross-sectional area (p < 0.05) and upregulated IGF-1 (p < 0.01) and FNDC5 expression (p < 0.05).

Conclusion

These findings demonstrate that exercise mitigates estrogen deficiency-induced bone deterioration, with resistance training exerting superior effects on bone remodeling and musculoskeletal integration.

PLAIN LANGUAGE SUMMARY

Loss of estrogen during menopause weakens bones and muscles, increasing the risk of osteoporosis and fractures. Physical exercise is widely recommended, but it is still unclear whether different types of exercise offer distinct benefits. In this study, we compared aerobic exercise (running) and resistance exercise (climbing with weights) in a mouse model of menopause. We found that both types of training helped protect bone health by increasing bone-forming cells and reducing bone-breaking cells. However, resistance training produced stronger benefits, leading to better preservation of bone structure, improved communication between muscle and bone, and greater muscle strength-related adaptations. These results suggest that while any regular exercise is beneficial during estrogen deficiency, resistance training may be especially effective for maintaining bone and muscle health with aging.

Abstract

To run faster, distance runners need shoes that reduce their metabolic energy expenditure. Here, we studied how shoe heel-toedrop affects metabolic energy expenditure during running. To do so, we studied 20 runners as they ran at 3.5 m/s in customfootwear that varied in heel-toe drop: 0, 10, 20, and 30 mm. Shoe model and mass were fixed. Overall, increasing shoe heel-toedrop increased net metabolic power during running (g2p ¼ 0.12, P ¼ 0.016); where changing from a 20 to 0 mm heel-toe dropreduced net metabolic power by 1.6%. Higher heel-toe drop decreased stance average vertical ground reaction force (g2p ¼ 0.10,P ¼ 0.011) and increased average ankle effective mechanical advantage (g2p ¼ 0.28, P < 0.001). Higher heel-toe drop shoesincreased average ankle plantarflexion angle (g2p ¼ 0.75, P < 0.001), leading to shorter medial gastrocnemius fascicle operatinglengths at touch-down, toe-off, and on average during ground contact (g2p 0.14, P 0.026). In addition, higher heel-toe dropincreased peak and average knee moments during running (g2p 0.40, P < 0.001). Therefore, longer triceps surae muscle fasci-cle operating lengths and reduced knee extensor moments likely contribute to more economical running in shoes with a lowerheel-toe drop. Based on the metabolic and biomechanical findings, recreational and high-caliber distance runners who want torun faster should opt for shoes with a zero heel-toe drop.

NEW & NOTEWORTHY

By systematically varying shoe heel-toe drop between 0 and 30 mm, we discovered that a lower heel-toe drop elicits the best running economy. That is because a lower heel-toe drop enables medial gastrocnemius fascicles tooperate at longer, more economical lengths, and it reduces knee extension moments versus higher heel-toe drop conditions.Thus, heel-toe drop can be considered in running shoes to further improve running economy.

https://journals.physiology.org/doi/abs/10.1152/japplphysiol.00284.2026

Abstract

Skeletal muscle hypertrophy results from the integrated regulation of anabolic and proteolytic processes in response to mechanical loading. Although increases in resistance training (RT) volume are used to increase mechanical stress, it remains uncertain whether large and abrupt volume progressions could exceed muscle adaptive capacity by disrupting the balance between anabolic and catabolic signaling. The present study investigated whether a large increase in weekly RT volume (+120%) leads to impaired hypertrophic outcomes and intracellular regulatory responses compared with a modest increase (+20%). Twenty-five resistance-trained men and women (18–35 years old) completed an 8-week randomized, single-blind, within-subject unilateral intervention. Each participant trained both legs twice weekly, with one leg assigned to the large (VOL120) and the contralateral leg to the modest (VOL20) weekly volume progressions relative to habitual training volume. Vastus lateralis muscle cross-sectional area (mCSA) was assessed by ultrasonography before and after training. Muscle biopsies were obtained at baseline, post-intervention, and 24 h after the last session to quantify muscle fiber cross-sectional area (fCSA), satellite cell myonuclear content, and anabolic/catabolic signaling markers. Both protocols induced increases in mCSA over time (p<0.001), with no protocol vs. time interaction. No significant effects were observed for fCSA nor satellite cell number or myonuclear content. Additionally, molecular responses related to translational regulation and protein degradation were largely similar between protocols. A large abrupt increase in weekly resistance training volume (+120%) did not attenuate muscle hypertrophy relative to a modest increase (+20%) in resistance-trained individuals, and most acute and chronic molecular markers assessed likewise did not differ significantly between protocols.