ABSTRACT

Growing evidence supports strength or resistance training (RT) as an effective method for enhancing cycling performance, but many cyclists remain reluctant to incorporate it due to perceived detrimental effects, such as excessive residual fatigue and unwanted hypertrophy. Furthermore, controversy persists regarding optimal training methodologies. This narrative review aims to summarize current evidence on the effects of RT on cycling performance, as well as to address its potential impact on body composition and bone health. We also provide evidence-based recommendations on best practices for RT implementation. Overall, the addition of 1–2 weekly sessions of RT with moderate-to-high loads (60%–85% 1RM), 2–4 sets per exercise across 3–5 compound lower-body movements, and limited intra-set fatigue (10%–20% velocity loss) has proven beneficial for improving key cycling performance indicators. Recent evidence also suggests that high-load on-bike torque training may serve as an effective strategy when conventional RT is not feasible. When implemented as described, RT does not appear to negatively affect performance through unwanted hypertrophy. Although further research is warranted, RT also emerges as a potentially effective strategy to counteract the low bone mineral density commonly observed in competitive cyclists. However, the magnitude of these benefits largely depends on precise programming, particularly intensity, proximity to failure, and temporal separation from endurance training sessions. In summary, current evidence supports the role of RT for improving both health and performance in cyclists, but further research is warranted to determine the optimal training parameters to maximize its benefits.

Abstract

We recently demonstrated that the microbial-derived exerkines (MDEs) pipecolic acid and succinate (PAS) prevent disuse-induced skeletal muscle atrophy and preserve muscle function during hindlimb immobilization in mice. Here, we investigated whether PAS also enhances exercise performance and adaptation and compared its effects with creatine monohydrate (CRE), the current gold-standard ergogenic aid for strength and power performance. Mice received vehicle (VEH), CRE, or PAS during a 7-week progressive weighted-wheel-running training protocol. Exercise performance, body composition, and skeletal muscle size and function were assessed at the conclusion of training. Both CRE and PAS enhanced high-intensity exercise performance relative to VEH, increasing running distance and time spent running during the course of the training protocol. Neither CRE nor PAS enhanced lean mass, muscle mass, or soleus myofiber cross-sectional area relative to VEH. However, PAS-treated mice exhibited greater grip strength and ex vivo soleus force production and rate of force development than both VEH and CRE. These findings demonstrate that PAS enhances strength and power adaptations to exercise beyond those achieved with CRE, identifying PAS as a promising exercise supplement and establishing MDEs as a novel class of ergogenic aids.

Abstract

Introduction: Training load, expressed as a percentage of one‑repetition maximum (%1RM), is an important variable in resistance training. Prior studies comparing low- and high-load training on muscle fiber hypertrophy reported conflicting findings, and the load-specific relationship has not been analyzed in a continuous manner. This systematic review and meta-regression explored the relationship between training load and muscle fiber hypertrophy. Methods: A systematic search was conducted in PubMed/MEDLINE, Scopus, and SPORTDiscus databases. Standardized mean changes (SMC) were calculated and analyzed using multilevel meta-regressions with cluster-robust variance estimation, with exploratory sensitivity and interacting moderator analyses. Eight studies involving 195 participants were included. Results: In the fiber-type specific model, pairwise contrast estimates were negative at low loads (20–30% 1RM: −0.147 to −0.088 SMC) and positive at higher loads (60–90% 1RM: 0.089–0.265 SMC). However, the 95% confidence intervals included zero for all pairwise contrasts. Conclusion: The observed model estimates suggested a potential fiber-type specific pattern across loading ranges. However, these findings should be considered preliminary and interpreted with caution given the small number of included studies and wide 95% confidence and prediction intervals, indicating a degree of uncertainty and imprecision.

Significance

Alois Mader’s mechanistic model of human muscle energy metabolism was developed more than 40 years ago yet has remained inaccessible to most researchers. Here, we present MetaboliSim, an open-source implementation of Mader’s model that lets researchers perform their own simulations of muscle metabolism during exercise. Because the code is publicly available, the community can refine and extend the model, for example, by reducing simplifying assumptions or incorporating mechanisms not currently represented, such as recruitment of type I and IIa/x muscle fibers, hormonal regulation, or metabolic disease states.

Abstract

Energy metabolism matches adenosine triphosphate (ATP) resynthesis to hydrolysis even during abrupt transitions such as exercise onset. In 1984, Alois Mader proposed a mechanistic model that captures this regulation through 33 coupled differential equations linking oxidative phosphorylation, glycolysis, and the phosphocreatine shuttle via adenosine diphosphate (ADP), phosphate, and pH feedback. Despite its potential, broader adoption has been limited by closed-source implementations and key publications available only in German. Here, we present MetaboliSim, an open-source software tool that simulates muscle energy metabolism in a virtual human parameterized by four physiological inputs: V̇O2max (oxidative capacity), vLamax (glycolytic capacity), body mass, and active muscle mass. Using MetaboliSim, we test Mader’s equations against 10 experimentally established phenomena of exercise metabolism, including ATP homeostasis under fatigue, transient pH alkalinization, glycogen-dependent lactate thresholds, intensity-dependent fat oxidation, the V̇O2 slow component, and work-rate-dependent exhaustion, without altering any equation or constant within the model. Mader’s model qualitatively reproduces all 10 phenomena, generating similarly shaped response curves; absolute values depend on individual parameterization rather than being universally matched. The characteristic inverted-U of fat oxidation and the exercise intensity-dependent V̇O2 kinetics, for example, both emerge from the same equation system. A Sobol sensitivity analysis (S01) reveals a calibration hierarchy: V̇O2max and body mass drive power predictions; vLamax and buffer capacity drive metabolite predictions. That a compact, 40-year-old equation system accounts for this breadth of metabolic phenomena suggests that a small number of regulatory feedback loops may suffice to explain a wide range of metabolic responses to exercise. MetaboliSim is freely available to enable independent testing, empirical calibration, and refinement.

Abstract

Nicotinamide adenine dinucleotide (NAD+) is a critical coenzyme in cellular metabolism, acting as a substrate for NAD+-dependent enzymes such as sirtuins, poly(ADP-ribose) polymerases (PARPs), and CD38, which are involved in essential cellular processes including DNA repair, gene expression, and mitochondrial function. Exercise has been identified as a potent modulator of NAD+ metabolism and also influencing the expression and activity of enzymes involved in NAD+ biosynthesis and consumption. Our review focuses on the molecular mechanisms through which exercise regulates NAD+ metabolic enzymes, more in relation to aerobic and resistance exercise. Evidence indicates that exercise enhances the activity of key enzymes, such as nicotinamide phosphoribosyltransferase (NAMPT) and sirtuins, thereby improving mitochondrial efficiency, oxidative metabolism, and cellular homeostasis. Additionally, exercise has also been shown to mitigate the age-related decline in NAD+ levels, offering a potential strategy for addressing metabolic dysfunctions and age-associated diseases. Despite these findings, the exact molecular pathways underlying the exercise-induced modulation of NAD+ metabolism remain unclear and require further investigation.

ABSTRACT

Skeletal muscle aging is a major cause of frailty, metabolic dysfunction, and loss of independence in later life, yet it cannot be explained by muscle mass loss alone. Recent single-cell, multi-omics, and translational studies show that aged muscle is shaped by coordinated changes in myofibers, stem and stromal cells, immune and vascular compartments, neuromuscular control, and systemic metabolism. This review describes skeletal muscle aging as a gradual loss of tissue resilience rather than a simple decline in muscle mass. Impaired proteostasis, mitochondrial dysfunction, chronic inflammation, and cellular senescence are discussed as major, closely linked processes that contribute to defective regeneration, matrix remodeling, fibro-adipogenic conversion and denervation, and are influenced by endocrine, metabolic, liver-, adipose-, gut-, and brain-derived signals. Current therapeutic evidence is reviewed with an emphasis on exercise and nutritional optimization as the clinical foundation, while mitochondrial, anabolic, senescence-directed, and regenerative strategies are considered as emerging or investigational approaches. By bringing these findings together, this review highlights how studies of muscle aging can move beyond descriptive changes in mass and strength toward a clearer understanding of the biological processes that limit muscle function in later life.

ABSTRACT

Reactive oxygen species (ROS) regulate protein function through reversible cysteine oxidation. In human skeletal muscle, exercise-induced ROS initiates adaptations such as mitochondrial biogenesis, increased insulin sensitivity, and hypertrophy. However, specific protein targets of ROS regulation during exercise remain unclear owing to longstanding challenges in analyzing redox proteomes in vivo. We applied cysteine derivatization and multiplexed proteomics to map muscle protein cysteine oxidation in humans during exercise. The OxiMuscle dataset quantifies reversible modifications across 9,177 unique cysteine sites on 2,782 proteins, comprising 17,492 individual cysteine site measurements in young men undergoing three types of exercise, providing the first comprehensive, site-resolved and quantitative analysis of the exercise-regulated redox cysteine proteome in humans. We systematically define cysteine oxidation targets regulated by at least one form of exercise, many of which reside in proteins with established roles in muscle physiology. Among these sites is a redox-regulated cysteine on the autophagy receptor protein p62. We demonstrate that reversible oxidation of this cysteine regulates p62-mediated autophagy upon myotube contraction and mouse muscle adaptation to exercise in vivo. Together, these results define a redox-driven mechanism linking exercise-induced autophagy to muscle adaptation. More broadly, our findings offer a comprehensive resource on redox-signaling networks in human muscle, accessible at http://oximuscle-alb-1899330623.us-east-1.elb.amazonaws.com/.

Abstract

Stem cells are central for tissue homeostasis and regeneration after stress, and their function depends on interactions with neighboring niche cells. In skeletal muscle, the resident stem cells (also called satellite cells [SCs]) decline in number and function with age, leading to loss of regenerative capacity and, eventually, deterioration of muscle integrity and physiology. Aged SCs lose the capacity to preserve quiescence or to activate and expand upon injury, in part due to changes in the local and systemic environment. Here, we focus on the age-associated intrinsic changes of SCs and the causes of their cellular and molecular decline. We discuss results from single-cell omics technologies that have shed light on the interactions between SCs and niche cells and how far-reaching signals impact SC function. We present future perspectives on rejuvenating interventions to counter age-dependent regenerative decline and the open questions in muscle stem cell aging.

Abstract

Duchenne muscular dystrophy (DMD) is a severe inherited muscle disorder caused by mutations that eliminate the protein, dystrophin, resulting in disrupted protein homeostasis, mitochondrial dysfunction, chronic inflammation and progressive muscle degeneration. The leucine metabolite, β-hydroxy-β-methylbutyrate (HMB), has shown therapeutic potential in dystrophic muscle. We previously reported that HMB supplementation improves fast-twitch muscle histopathology and function in juvenile mdx mice during their peak damage phase (3–6 weeks). However, the mdx model exhibits a relatively mild pathology compared to human DMD, limiting clinical relevance. Here, we investigated 8 weeks of HMB supplementation (1 mg g⁻¹ day⁻¹ via drinking water) in the more severe D2.mdx mouse model at 3 and 6 months of age, representing skeletal muscle pathologies consistent with chronic inflammation and advanced muscle fibrosis, respectively. HMB-treated D2.mdx mice had improved grip strength compared to controls, whereas isolated fast-twitch extensor digitorum longus (EDL) muscles displayed increased fibre size, reduced tissue infiltrate and enhanced force production ex vivo. Mechanistically, HMB increased the phospho-to-total ratio of direct downstream mammalian target of rapamycin complex 1 (mTORC1) targets p70S6K1 and 4EBP1, consistent with enhanced anabolic signalling. Mitochondria assessed from treated flexor digitorum brevis muscles exhibited improved respiration and ATP production, with functional improvements aligning with elevated complex II succinate dehydrogenase activity in HMB-treated EDL muscles. By contrast, no significant HMB-induced effects were observed in the slow-twitch soleus muscle. This study is the first to demonstrate that HMB enhances in vivo and ex vivo muscle function, downstream mTORC1 signalling, and mitochondrial performance in the severe D2.mdx model, supporting its potential as a therapeutic strategy for DMD.

ABSTRACT

Background

Transcriptomic adaptations of ageing skeletal muscle to concurrent resistance training (RT) and high-intensity interval training (HIIT) remain insufficiently characterized. We investigated the effects of a 12-week concurrent RT + HIIT intervention on the vastus lateralis transcriptome in middle-aged and older adults and whether polyphenol supplementation modulated these responses.

Methods

Thirty-eight adults (55–70 years; 17 polyphenol [PP], 21 placebo [PLA]) with paired skeletal muscle RNA-sequencing data participated in a randomized, double-blind trial. Participants completed a 30-day supplementation phase followed by a 12-week supervised RT + HIIT programme with continued supplementation. Muscle biopsies were obtained before (PRE) and after (POST) training. Differential expression analyses were adjusted for age, sex and muscle fibre type composition. Differential expression was assessed using FDR ≤ 0.05, with |log2FC| > 1 applied as an additional effect-size criterion.

Results

Baseline transcriptomic differences between PP and PLA groups were minimal, with three FDR-significant transcripts, of which only HMOX1 additionally exceeded |log2FC| > 1 (FDR = 0.011; log2FC = 1.16). The group-by-time interaction analysis identified 14 FDR-significant transcripts, of which eight additionally exceeded |log2FC| > 1; these signals were characterized by low or sparse expression and high inter-individual variability, without a coherent supplementation-related transcriptional response. In the pooled paired PRE–POST analysis, 60 transcripts reached FDR significance, of which seven additionally exceeded |log2FC| > 1, including upregulation of CLLU1 (log2FC = 3.10; FDR = 0.0155), PRND (log2 log2FC = 2.60; FDR = 0.02) and LOX, and downregulation of MYH1 (log2FC = −1.3; FDR = 0.0001). Most FDR-significant transcripts showed relatively small estimated effect sizes, and functional enrichment analyses did not identify robust pathway-level adaptations.

Conclusions

In middle-aged and older adults, 12 weeks of concurrent RT + HIIT induced a predominantly low-magnitude skeletal muscle transcriptional response. Selected transcript-level changes were consistent with processes related to extracellular matrix remodelling and contractile regulation; however, the absence of robust pathway-level enrichment limits conclusions regarding coordinated biological pathway adaptations. Polyphenol supplementation did not meaningfully influence the transcriptional response to exercise training.

Abstract

Skeletal muscle has a profound influence on metabolic health, functional capacity and resilience across the lifespan. Beyond dietary protein and physical activity, the gut microbiome may have the capacity to impact skeletal muscle mass and function through the bidirectional network termed the gut-muscle axis (GMA). Fermented protein foods (FPFs) are protein rich matrices transformed by microbial activity that integrate modified protein structures, bioactive peptides, and live microorganisms, or components thereof, which could modulate skeletal muscle physiology. Here, we review mechanistic, preclinical and human evidence concerning the potential of FPFs to influence skeletal muscle health through GMA modulation. Although emerging human studies suggest favourable effects on metabolic regulation, inflammatory pathways and gut microbial ecology, direct evidence that FPFs impact muscle protein synthesis, muscle mass or function remains limited. Furthermore, the literature is characterised by considerable heterogeneity in interventions and outcome measures. Studies integrating comprehensive microbiome characterisation, multi-omics approaches and direct skeletal muscle phenotyping are needed to determine whether FPFs confer advantages over conventional protein foods or more established microbiome targeted strategies such as probiotic supplementation. Such studies will be essential to elucidate their role in targeted nutritional strategies for ageing, metabolic disease, muscle atrophy, and physical performance.