Muscle Hypertrophy In Response Research Articles

Muscle-Derived microRNAs Correlated with Thigh Lean Mass Gains during Progressive Resistance Training in Older Adults.

Resistance training (RT) remains the most effective treatment for age-related declines in muscle mass. However, many older adults experience attenuated muscle hypertrophy in response to RT when compared to younger adults. This may be attributed to underlying molecular processes that are dysregulated by aging and exacerbated by improperly prescribed RT weekly volume, intensity, and/or frequency doses. MicroRNA (miRNA) are key epigenetic regulators that impact signaling pathways and protein expression within cells, are dynamic and responsive to exercise stimuli, and are often dysregulated in diseases. In this study, we used untargeted miRNA-seq to examine miRNA in skeletal muscle and serum-derived exosomes of older adults (n = 18, 11M/7F, 66±1y) who underwent 3x/wk RT for 30 weeks [e.g., high intensity 3x/wk (HHH, n = 9) or alternating high-low-high intensity (HLH, n = 9)], after a standardized four-week wash-in. Within each tissue, miRNAs were clustered into modules based on pairwise correlation using Weighted Gene Correlation Network Analysis (WGCNA). Modules were tested for association with the magnitude of RT-induced thigh lean mass (TLM) change (as measured by DXA). While no modules were unique to training dose, we identified miRNA modules in skeletal muscle associated with TLM gains irrespective of exercise dose. Using miRNA-target interactions, we analyzed key miRNAs in significant modules for their potential regulatory involvement in biological pathways. Findings point toward potential miRNAs that may be informative biomarkers and could also be evaluated as potential therapeutic targets as an adjuvant to RT in order to maximize skeletal muscle mass accrual in older adults.

Higher resistance training volume offsets muscle hypertrophy nonresponsiveness in older individuals.

The magnitude of muscle hypertrophy in response to resistance training (RT) is highly variable between individuals (response heterogeneity). Manipulations in RT variables may modulate RT-related response heterogeneity; yet, this remains to be determined. Using a within-subject unilateral design, we aimed to investigate the effects of RT volume manipulation on whole muscle hypertrophy [quadriceps muscle cross-sectional area (qCSA)] among nonresponders and responders to a low RT dose (single-set). We also investigated the effects of RT volume manipulation on muscle strength in these responsiveness groups. Eighty-five older individuals [41M/44F, age = 68 ± 4 yr; body mass index (BMI) = 26.4 ± 3.7 kg/m2] had one leg randomly allocated to a single (1)-set and the contralateral leg allocated to four sets of unilateral knee-extension RT at 8-15 repetition maximum (RM) for 10-wk 2 days/wk. Pre- and postintervention, participants underwent magnetic resonance imaging (MRI) and unilateral knee-extension 1-RM strength testing. MRI typical error (2× TE = 3.27%) was used to classify individuals according to responsiveness patterns. n = 51 were classified as nonresponders (≤2× TE) and n = 34 as responders (>2× TE) based on pre- to postintervention change qCSA following the single-set RT protocol. Nonresponders to single-set training showed a dose response, with significant time × set interactions for qCSA and 1-RM strength, indicating greater gains in response to the higher volume prescription (time × set: P < 0.05 for both outcomes). Responders improved qCSA (time: P < 0.001), with a tendency toward higher benefit from the four sets RT protocol (time × set: P = 0.08); on the other hand, 1-RM increased similarly irrespectively of RT volume prescription (time × set: P > 0.05). Our findings support the use of higher RT volume to mitigate nonresponsiveness among older adults.NEW & NOTEWORTHY Using a within-subject unilateral design, we demonstrated that increasing resistance training (RT) volume may be a simple, effective strategy to improve muscle hypertrophy and strength gains among older adults who do not respond to low-volume RT. In addition, it could most likely be used to further improve hypertrophic outcomes in responders.

Sex Differences in Muscle Hypertrophy Response to Training of the Peroneus Longus and Peroneus Brevis Muscles

Category: Ankle; Trauma Introduction/Purpose: It has been reported that there are no significant sex differences in muscle hypertrophy response after strength training for the quadriceps muscles (Roth et al., 2002). After an ankle sprain, the peroneus longus (PL) and peroneus brevis (PB) muscles develop morphological changes and dysfunction, which requires training for the PL and PB (Arima et al., 2022). However, to our knowledge, sex differences in muscle hypertrophic response to the PL and PB training have not been studied. This study aimed to compare the changes in muscle cross-sectional area (CSA) after the PL and PB training between men and women, and to examine the possible influence of sex on the muscle hypertrophy response to training for the PL and PB. Methods: Eighteen healthy adults (9 men and 9 women) were participated. All participants performed two types of ankle eversion training on the right leg with Thera-Band on separate days. PL training in which the Thera-Band was placed on the ball of foot and pushed out from the contact point, and PB training in which the Thera-Band was pushed out from the base of the fifth metatarsal. An ultrasound imaging device was used to measure the CSA of the peroneal muscles at the proximal 25% and distal 75% of the line connecting the fibular head and the lateral malleolus. The measurements were taken before (pre), immediately after (post), 10, 20, and 30 minutes after each training, and the amount of change over time relative to pre was calculated. Unpaired t-tests were used to compare the change in CSA between men and women at each time. Statistical significance was set at 5%. Results: After the PL training, the amount of change in CSA of the PL was significantly greater by 29.7 mm² in women than in men only at post (p &lt; 0.05), but there were no significant differences at other times (10 minutes: p = 0.06, 20 minutes: p = 0.19, 30 minutes: p = 0.11). After the PB training, the amount of change in CSA of the PB was significantly greater by 16.0 mm² at post (p &lt; 0.05) and 3.1 mm² at 30 minutes (p &lt; 0.01) in women than in men. However, there were no significant differences at 10 and 20 minutes (10 minutes: p = 0.27, 20 minutes: p = 0.55). Conclusion: The results indicate that sex differences may influence the immediate muscle hypertrophic response to training for the PL and PB. The immediate muscle hypertrophy response after training is due to edema resulting from muscle damage, reflecting an immediate effect of training (Damas et al., 2016), which suggests that women are more likely to achieve effects of the PL and PB training than men in similar loads. Furthermore, the results also show that the effect of the PB training may be maintained longer in women, thus it is necessary to investigate the long-term effects of the training in the future.

The Importance of Previous Resistance Training Volume on Muscle Growth in Trained Individuals

ABSTRACT Resistance training volume has been suggested to be one of the most effective variables for developing muscular hypertrophy. Meta-analyses have concluded that there exists a dose-response relationship between weekly resistance training volume (i.e., the number of sets performed over the training week) and muscle mass accrual in nonresistance-trained individuals; however, experimental data in resistance-trained individuals have shown conflicting results. Current literature suggests that the performance of additional sets of resistance exercise within a single training session and training week does not inherently result in greater increases in muscle size compared with groups or conditions that perform lower volumes of resistance training. Notwithstanding these results, it has been suggested that controlling for each individual's previous training volume could improve the precision of the muscle hypertrophic response to resistance training and that failing to do so would disregard the principle of progressive overload. Herein, we explore the evidence for the suggestion that a higher-volume approach to training, in comparison to what an individual has been accustomed to, would improve the precision of the muscle growth response to resistance training and the physiological rationale that may (or may not) underpin this phenomenon.

Does the blunted stimulation of skeletal muscle protein synthesis by aging in response to mechanical load result from impaired ribosome biogenesis?

Age-related loss of skeletal muscle mass leads to a reduction of strength. It is likely due to an inadequate stimulation of muscle protein synthesis (MPS) in response to anabolic stimuli, such as mechanical load. Ribosome biogenesis is a major determinant of translational capacity and is essential for the control of muscle mass. This mini-review aims to put forth the hypothesis that ribosome biogenesis is impaired by aging in response to mechanical load, which could contribute to the age-related anabolic resistance and progressive muscle atrophy. Recent animal studies indicate that aging impedes muscle hypertrophic response to mechanical overload. This is associated with an impaired transcription of ribosomal DNA (rDNA) by RNA polymerase I (Pol I), a limited increase in total RNA concentration, a blunted activation of AKT/mTOR pathway, and an increased phosphorylation of AMPK. In contrast, an age-mediated impairment of ribosome biogenesis is unlikely in response to electrical stimulations. In human, the hypertrophic response to resistance exercise training is diminished with age. This is accompanied by a deficit in long-term MPS and an absence of increased total RNA concentration. The results addressing the acute response to resistance exercise suggest an impaired Pol I-mediated rDNA transcription and attenuated activation/expression of several upstream regulators of ribosome biogenesis in muscles from aged individuals. Altogether, emerging evidence indicates that impaired ribosome biogenesis could partly explain age-related anabolic resistance to mechanical load, which may ultimately contribute to progressive muscle atrophy. Future research should develop more advanced molecular tools to provide in-depth analysis of muscle ribosome biogenesis.

Similar Responses in the Akt/Protein Kinase B Signaling Pathway Following Different Lower-Body Exercise Volumes in Recreationally Active Men.

Pearson, JR, Moodie, N, Stout, KW, Hawkins, WC, Matuszek, M, Graham, ZA, Siedlik, JA, Vardiman, JP, and Gallagher, PM. Similar responses in the Akt/protein kinase B (PKB) signaling pathway after different lower-body exercise volumes in recreationally active men. J Strength Cond Res 37(5): 1034-1041, 2023-This project examined the differences between a single set (SS) compared to multiple sets (MS) of resistance exercise on the Akt/protein kinase B (PKB) signaling pathway, the expression of insulin-like growth factor-1 ( IGF-1 ), and the receptor for IGF -1 ( IGF-1R ) to better understand the types of resistance training protocols that are most beneficial in stimulating the muscle hypertrophic response. Sixteen healthy men were randomly selected into 2 groups of 8. Subjects in each group received 3 biopsies: (a) before exercise, (b) 15 minutes postexercise, and (c) 180 minutes postexercise. Subjects in the SS group performed 1 set of leg press to failure at 80% of their predetermined 1 repetition maximum (1RM). Subjects in the MS group performed 2 sets of 10 repetitions and 1 set to failure at 80% of their predetermined 1RM, with 3 minutes of rest between each set. Our results indicated no group × time interactions in the concentration of Akt signaling proteins. Furthermore, there were no group × time interactions in IGF-1 or IGF-1R expression. However, phosphorylated 4E-binding protein 1 levels increased 150% from pre to 180 minutes post ( p = 0.005). In addition, there was a significantly greater increase in IGF-1R expression in the SS group compared with the MS group (7.99 ± 10.07 vs. 4.41 ± 6.28; p = 0.026). Collectively, we found that a SS of resistance training evokes a similar acute Akt/PKB pathway response as MS in recreationally active men.

Effects of transdermal estrogen therapy on satellite cell number and molecular markers for muscle hypertrophy in response to resistance training in early postmenopausal women.

To investigate the effects of resistance training with or without transdermal estrogen therapy (ET) on satellite cell (SC) number and molecular markers for muscle hypertrophy in early postmenopausal women. Using a double-blinded randomized controlled design, we allocated healthy, untrained postmenopausal women to perform 12weeks of resistance training with placebo (PLC, n = 16) or ET (n = 15). Muscle biopsies obtained before and after the intervention, and two hours after the last training session were analyzed for fiber type, SC number and molecular markers for muscle hypertrophy and degradation (real-time PCR, western blotting). The analysis of SCs per Type I fiber showed a time x treatment interaction caused by a 47% decrease in PLC, and a 26% increase after ET after the training period. Also, SCs per Type II fiber area was lower after the intervention driven by a 57% decrease in PLC. Most molecular markers changed similarly in the two groups. A decline in SC per muscle fiber was observed after the 12-week training period in postmenopausal women, which was counteracted when combined with use of transdermal ET. nct03020953.

Effects of lactate administration on hypertrophy and mTOR signaling activation in mouse skeletal muscle.

Lactate is a metabolic product of glycolysis and has recently been shown to act as a signaling molecule that induces adaptations in oxidative metabolism. In this study, we investigated whether lactate administration enhanced muscle hypertrophy and protein synthesis responses during resistance exercise in animal models. We used male ICR mice (7–8 weeks old) were used for chronic (mechanical overload induced by synergist ablation: [OL]) and acute (high‐intensity muscle contraction by electrical stimulation: [ES]) resistance exercise models. The animals were intraperitoneally administrated a single dose of sodium lactate (1 g/kg of body weight) in the ES study, and once a day for 14 consecutive days in the OL study. Two weeks of mechanical overload increased plantaris muscle wet weight (main effect of OL: p < 0.05) and fiber cross‐sectional area (main effect of OL: p < 0.05), but those were not affected by lactate administration. Following the acute resistance exercise by ES, protein synthesis and phosphorylation of p70 S6 kinase and ribosomal protein S6, which are downstream molecules in the anabolic signaling cascade, were increased (main effect of ES: p < 0.05), but lactate administration had no effect. This study demonstrated that exogenous lactate administration has little effect on the muscle hypertrophic response during resistance exercise using acute ES and chronic OL models. Our results do not support the hypothesis that elevated blood lactate concentration induces protein synthesis responses in skeletal muscle.

Impact of methionine restriction on muscle aerobic metabolism and hypertrophy in young and old mice on an obesogenic diet

Methionine restriction (MR) reduces inflammation and increases longevity. We studied the effects of MR (0.17% kCal methionine, 10% kCal fat) and MR + high-fat diet (HFD) (0.17% methionine, 45% kCal fat) and overload-induced hypertrophy on inflammation, angiogenesis and mitochondrial activity in the hind-limb muscle in 10- and 26-month-old male C57BL/6J mice. Plasma IL-6 concentrations were higher in old compared to young mice. M. plantaris hypertrophy was accompanied by increased p-Akt, without a significant change in Akt and VEGF levels. In young mice on a HFD or MR + HFD diet the SDH activity was higher than in those from mice on other diets, irrespective of overload. There were no significant differences in total NAD concentration in the m. gastrocnemius. MR enhanced the skeletal muscle hypertrophic response in old age that was accompanied with an increase in p-Akt without significant changes in muscle oxidative capacity, low-grade systemic inflammation, NAD, VEGF or Akt levels.

CCN2 participates in overload-induced skeletal muscle hypertrophy

The regulation of skeletal muscle growth following pro-hypertrophic stimuli requires a coordinated response by different cell types that leads to extracellular matrix (ECM) remodeling and increases in muscle cross-sectional area. Indeed, matricellular proteins serve a key role as communication vehicles that facilitate the propagation of signaling stimuli required for muscle adaptation to environmental challenges. We found that the matricellular protein cellular communication network factor 2 (CCN2), also known as connective tissue growth factor (CTGF), is induced during a time course of overload-driven skeletal muscle hypertrophy in mice. To elucidate the role of CCN2 in mediating the hypertrophic response, we utilized genetically engineered mouse models for myofiber-specific CCN2 gain- and loss-of-function and then examined their response to mechanical stimuli through muscle overload. Interestingly, myofiber-specific deletion of CCN2 blunted muscle's hypertrophic response to overload without interfering with ECM deposition. On the other hand, when in excess through transgenic CCN2 overexpression, CCN2 was efficient in promoting overload-induced aberrant ECM accumulation without affecting myofiber growth. Altogether, our genetic approaches highlighted independent ECM and myofiber stress adaptation responses, and positioned CCN2 as a central mediator of both. Mechanistically, CCN2 acts by regulating focal adhesion kinase (FAK) mediated transduction of overload-induced extracellular signals, including interleukin 6 (IL6), and their regulatory impact on global protein synthesis in skeletal muscle. Overall, our study highlights the contribution of muscle-derived extracellular matrix factor CCN2 for proper hypertrophic muscle growth.

Muscle transcriptional networks linked to resistance exercise training hypertrophic response heterogeneity.

The skeletal muscle hypertrophic response to resistance exercise training (RT) is highly variable across individuals. The molecular underpinnings of this heterogeneity are unclear. This study investigated transcriptional networks linked to RT-induced muscle hypertrophy, classified as 1) predictive of hypertrophy, 2) responsive to RT independent of muscle hypertrophy, or 3) plastic with hypertrophy. Older adults (n = 31, 18 F/13 M, 70 ± 4 yr) underwent 14-wk RT (3 days/wk, alternating high-low-high intensity). Muscle hypertrophy was assessed by pre- to post-RT change in mid-thigh muscle cross-sectional area (CSA) [computed tomography (CT), primary outcome] and thigh lean mass [dual-energy X-ray absorptiometry (DXA), secondary outcome]. Transcriptome-wide poly-A RNA-seq was performed on vastus lateralis tissue collected pre- (n = 31) and post-RT (n = 22). Prediction networks (using only baseline RNA-seq) were identified by weighted gene correlation network analysis (WGCNA). To identify Plasticity networks, WGCNA change indices for paired samples were calculated and correlated to changes in muscle size outcomes. Pathway-level information extractor (PLIER) was applied to identify Response networks and link genes to biological annotation. Prediction networks (n = 6) confirmed transcripts previously connected to resistance/aerobic training adaptations in the MetaMEx database while revealing novel member genes that should fuel future research to understand the influence of baseline muscle gene expression on hypertrophy. Response networks (n = 6) indicated RT-induced increase in aerobic metabolism and reduced expression of genes associated with spliceosome biology and type-I myofibers. A single exploratory Plasticity network was identified. Findings support that interindividual differences in baseline gene expression may contribute more than RT-induced changes in gene networks to muscle hypertrophic response heterogeneity. Code/Data: https://github.com/kallavin/MASTERS_manuscript/tree/master.

Loss of ARNT Limits Improvement in Physiological Performance Following Aerobic Exercise in Aging

Hypoxia signaling is essential for angiogenesis and metabolic regulation during exercise. Our previous study has demonstrated an age-related loss of ARNT resulting in limited muscle regeneration. To explore the role of hypoxia signaling in physiological performance in relation to aging, we generated a mouse model with skeletal muscle-specific knockout of ARNT (ARNT mKO). ARNT mKO and ARNT WT mice were subjected to a sedentary activity or treadmill running exercise regime at an increasing speed of 8-12 m/min for 40 minutes, three times weekly over the course of 8 weeks. ARNT levels was 3-fold lower in old mice compared to young. The exercised WT mice exhibited 52% greater increase over the sedentary group in exercise endurance as measured by the maximum running distance (490.92±154.28 vs 237.76±135.19m, p＜0.01). In contrast, ARNT mKO mice did not benefit from exercise (231.85±198.61 vs 167.27±136.56m, p=0.41). The maximum running speed was severely restricted in the trained ARNT mKO mice versus WT (16±1.63 m/min vs 26.67±2.45 m/min, p＜0.001). Cross-sectional area of myofibers increased significantly following exercise in WT mice (2270 vs 2960 □m2, p=0,015) indicating muscle hypertrophic response, while no change was observed in the ARNT mKO group (2101 vs 2378□m2, p=0,21). Further, exercise increased femoral artery blood flow by 41% in ARNT WT mice, but not in ARNT mKO mice (898.96±52.33 vs 802.86±48.43, p=0.20). These data suggest that ARNT is essential for physiological response to exercise

Metformin alters skeletal muscle transcriptome adaptations to resistance training in older adults.

Evidence from clinical trials and observational studies suggests that both progressive resistance exercise training (PRT) and metformin delay a variety of age-related morbidities. Previously, we completed a clinical trial testing the effects of 14 weeks of PRT + metformin (metPRT) compared to PRT with placebo (plaPRT) on muscle hypertrophy in older adults. We found that metformin blunted PRT-induced muscle hypertrophic response. To understand potential mechanisms underlying the inhibitory effect of metformin on PRT, we analyzed the muscle transcriptome in 23 metPRT and 24 plaPRT participants. PRT significantly increased expression of genes involved in extracellular matrix remodeling pathways, and downregulated RNA processing pathways in both groups, however, metformin attenuated the number of differentially expressed genes within these pathways compared to plaPRT. Pathway analysis showed that genes unique to metPRT modulated aging-relevant pathways, such as cellular senescence and autophagy. Differentially expressed genes from baseline biopsies in older adults compared to resting muscle from young volunteers were reduced following PRT in plaPRT and were further reduced in metPRT. We suggest that although metformin may blunt pathways induced by PRT to promote muscle hypertrophy, adjunctive metformin during PRT may have beneficial effects on aging-associated pathways in muscle from older adults.

Response of Resistance Exercise-Induced Muscle Protein Synthesis and Skeletal Muscle Hypertrophy Are Not Enhanced After Disuse Muscle Atrophy in Rat.

Skeletal muscle disuse rapidly decreases muscle mass. Resistance training (RT) is believed as the most effective way to gain muscle mass via an increase in mTORC1 activity and muscle protein synthesis (MPS). However, it remains unclear whether muscle atrophy by disuse alters the mTORC1 activation and MPS response to an acute resistance exercise (RE) and chronic RT–mediated skeletal muscle hypertrophy. This study investigated the influence of disuse muscle atrophy on the response of mTORC1 activation and MPS to an acute RE. We also evaluated whether disuse muscle atrophy affects the response of RT-induced muscle mass gain. Thirty male Sprague-Dawley rats were randomly divided into control (CON) or hindlimb suspension (HS) groups. A 14-day HS via the tail was used as the model for gastrocnemius muscle disuse in the HS group. Unilateral lower limb muscle contraction using by percutaneous electrical stimulation was used to mimic the stimuli of RE. Ten bouts of RE were performed in 3-week as chronic RT. Our results showed that MPS and mTORC1 activity was unchanged after HS at basal state. However, the ribosomal RNA (rRNA) level was reduced in HS rats compared to that in CON rats at basal state. MPS and rRNA increased in both HS and CON rats in response to acute RE to the same extent. However, the level of mTORC1 activation in response to an acute RE was significantly higher in HS than that in the CON group at 12 h after exercise, even though no difference was observed at 3 h after exercise. The 10-bout RT significantly increased gastrocnemius muscle mass in both CON and HS rats. The response of muscle hypertrophy did not differ between the groups. Therefore, MPS in response to acute RE and muscle hypertrophy in response to chronic RT were unaltered after disuse muscle atrophy.

Exercício resistido e hipertrofia regional da musculatura esquelética: revisão de literatura

A hipertrofia do musculo esquelético é caracterizada pelo aumento da área de secção transversal (AST) através de estímulos produzidos pelo exercício resistido (ER). Alguns trabalhos têm demonstrado que os ganhos da hipertrofia muscular esquelética em resposta ao ER ocorrem de forma não uniforme ao longo do músculo, este processo também é conhecido como hipertrofia regional. Este estudo foi constituído por meio de uma revisão bibliográfica. Utilizou-se para coleta a análise de artigos científicos, livros e pesquisas realizadas nas bases de dados do Scielo, LILACS e PubMed, abrangendo trabalhos internacionais. Os trabalhos na literatura são escassos em relação ao ER e hipertrofia regional nos diferentes grupos musculares, o quadríceps parece apresentar maior hipertrofia na região proximal e cadeira extensora nas regiões medial e distal. Já o tríceps a variação das angulações dos exercícios parece influenciar diretamente a hipertrofia regional. Por outro lado, o bíceps braquial parece ter maior aumento nas regiões medial e proximal sendo esta resposta influenciada pelo tipo de contração ou velocidade da execução do exercício. Em relação aos isquiotibiais e peitoral maior são insuficientes na literatura os estudos sobre a hipertrofia regional relacionados com estes músculos. Além disso, as diferenças na ativação muscular e a síntese de proteínas contráteis parecem ser os principais fatores responsáveis pelas respostas hipertróficas diferentes ao longo do músculo.

Resistance exercise training promotes fiber type-specific myonuclear adaptations in older adults.

Aging induces physiological decline in human skeletal muscle function and morphology, including type II fiber atrophy and an increase in type I fiber frequency. Resistance exercise training (RET) is an effective strategy to overcome muscle mass loss and improve strength, with a stronger effect on type II fibers. In the present study, we sought to determine the effect of a 12-wk progressive RET program on the fiber type-specific skeletal muscle hypertrophic response in older adults. Nineteen subjects [10 men and 9 women (71.1 ± 4.3 yr)] were studied before and after the 12-wk program. Immunohistochemical analysis was used to quantify myosin heavy chain (MyHC) isoform expression, cross-sectional area (CSA), satellite cell abundance, myonuclear content, and lipid droplet density. RET induced an increase in MyHC type II fiber frequency and a concomitant decrease in MyHC type I fiber frequency. Mean CSA increased significantly only in MyHC type II fibers (+23.3%, P < 0.05), but myonuclear content increased only in MyHC type I fibers (P < 0.05), with no change in MyHC type II fibers. Satellite cell content increased ~40% in both fiber types (P > 0.05). RET induced adaptations to the capillary supply to satellite cells, with the distance between satellite cells and the nearest capillary increasing in type I fibers and decreasing in type II fibers. Both fiber types showed similar decrements in intramuscular lipid density with training (P < 0.05). Our data provide intriguing evidence for a fiber type-specific response to RET in older adults and suggest flexibility in the myonuclear domain of type II fibers during a hypertrophic stimulus.NEW & NOTEWORTHY In older adults, progressive resistance exercise training (RET) increased skeletal muscle fiber volume and cross-sectional area independently of myonuclear accretion, leading to an expansion of the myonuclear domain. Fiber type-specific analyses illuminated differential adaptation; type II fibers underwent hypertrophy and exhibited myonuclear domain plasticity, whereas myonuclear accretion occurred in type I fibers in the absence of a robust hypertrophic response. RET also augmented satellite cell-capillary interaction and reduced intramyocellular lipid density to improve muscle quality.

Recent advances in understanding resistance exercise training-induced skeletal muscle hypertrophy in humans.

Skeletal muscle plays a pivotal role in the maintenance of physical and metabolic health and, critically, mobility. Accordingly, strategies focused on increasing the quality and quantity of skeletal muscle are relevant, and resistance exercise is foundational to the process of functional hypertrophy. Much of our current understanding of skeletal muscle hypertrophy can be attributed to the development and utilization of stable isotopically labeled tracers. We know that resistance exercise and sufficient protein intake act synergistically and provide the most effective stimuli to enhance skeletal muscle mass; however, the molecular intricacies that underpin the tremendous response variability to resistance exercise-induced hypertrophy are complex. The purpose of this review is to discuss recent studies with the aim of shedding light on key regulatory mechanisms that dictate hypertrophic gains in skeletal muscle mass. We also aim to provide a brief up-to-date summary of the recent advances in our understanding of skeletal muscle hypertrophy in response to resistance training in humans.

Acute environmental hypoxia potentiates satellite cell-dependent myogenesis in response to resistance exercise through the inflammation pathway in human.

Acute environmental hypoxia may potentiate muscle hypertrophy in response to resistance training but the mechanisms are still unknown. To this end, twenty subjects performed a 1-leg knee extension session (8 sets of 8 repetitions at 80% 1 repetition maximum, 2-min rest between sets) in normoxic or normobaric hypoxic conditions (FiO2 14%). Muscle biopsies were taken 15 min and 4 hours after exercise in the vastus lateralis of the exercised and the non-exercised legs. Blood samples were taken immediately, 2h and 4h after exercise. In vivo, hypoxic exercise fostered acute inflammation mediated by the TNFα/NF-κB/IL-6/STAT3 (+333%, +194%, + 163% and +50% respectively) pathway, which has been shown to contribute to satellite cells myogenesis. Inflammation activation was followed by skeletal muscle invasion by CD68 (+63%) and CD197 (+152%) positive immune cells, both known to regulate muscle regeneration. The role of hypoxia-induced activation of inflammation in myogenesis was confirmed in vitro. Acute hypoxia promoted myogenesis through increased Myf5 (+300%), MyoD (+88%), myogenin (+1816%) and MRF4 (+489%) mRNA levels in primary myotubes and this response was blunted by siRNA targeting STAT3. In conclusion, our results suggest that hypoxia could improve muscle hypertrophic response following resistance exercise through IL-6/STAT3-dependent myogenesis and immune cells-dependent muscle regeneration.

QuantiMus: A Machine Learning-Based Approach for High Precision Analysis of Skeletal Muscle Morphology.

Skeletal muscle injury provokes a regenerative response, characterized by the de novo generation of myofibers that are distinguished by central nucleation and re-expression of developmentally restricted genes. In addition to these characteristics, myofiber cross-sectional area (CSA) is widely used to evaluate muscle hypertrophic and regenerative responses. Here, we introduce QuantiMus, a free software program that uses machine learning algorithms to quantify muscle morphology and molecular features with high precision and quick processing-time. The ability of QuantiMus to define and measure myofibers was compared to manual measurement or other automated software programs. QuantiMus rapidly and accurately defined total myofibers and measured CSA with comparable performance but quantified the CSA of centrally-nucleated fibers (CNFs) with greater precision compared to other software. It additionally quantified the fluorescence intensity of individual myofibers of human and mouse muscle, which was used to assess the distribution of myofiber type, based on the myosin heavy chain isoform that was expressed. Furthermore, analysis of entire quadriceps cross-sections of healthy and mdx mice showed that dystrophic muscle had an increased frequency of Evans blue dye+ injured myofibers. QuantiMus also revealed that the proportion of centrally nucleated, regenerating myofibers that express embryonic myosin heavy chain (eMyHC) or neural cell adhesion molecule (NCAM) were increased in dystrophic mice. Our findings reveal that QuantiMus has several advantages over existing software. The unique self-learning capacity of the machine learning algorithms provides superior accuracy and the ability to rapidly interrogate the complete muscle section. These qualities increase rigor and reproducibility by avoiding methods that rely on the sampling of representative areas of a section. This is of particular importance for the analysis of dystrophic muscle given the “patchy” distribution of muscle pathology. QuantiMus is an open source tool, allowing customization to meet investigator-specific needs and provides novel analytical approaches for quantifying muscle morphology.

A porous collagen-GAG scaffold promotes muscle regeneration following volumetric muscle loss injury.

Volumetric muscle loss (VML) is a segmental loss of skeletal muscle which commonly heals with fibrosis, minimal muscle regeneration, and loss of muscle strength. Treatment options for these wounds which promote functional recovery are currently lacking. This study was designed to investigate whether the collagen-GAG scaffold (CGS) promotes functional muscle recovery following VML. A total of 66 C57/Bl6 mice were used in a three-stage experiment. First, 24 animals were split into three groups which underwent sham injury or unilateral quadriceps VML injury with or without CGS implantation. Two weeks post-surgery, muscle was harvested for histological and gene expression analysis. In the second stage, 18 mice underwent bilateral quadriceps VML injury, followed by weekly functional testing using a treadmill. In the third stage, 24 mice underwent sham or bilateral quadriceps VML injury with or without CGS implantation, with tissue harvested six weeks post-surgery for histological and gene expression analysis. VML mice treated with CGS demonstrated increased remnant fiber hypertrophy versus both the VML with no CGS and uninjured groups. Both VML groups showed greater muscle fiber hypertrophy than non-injured muscle. This phenomenon was still evident in the longer-term experiment. The gene array indicated that the CGS promoted upregulation of factors involved in promoting wound healing and regeneration. In terms of functional improvement, the VML mice treated with CGS ran at higher maximum speeds than VML without CGS. A CGS was shown to enhance muscle hypertrophy in response to VML injury with a resultant improvement in functional performance. A gene array highlighted increased gene expression of multiple growth factors following CGS implantation. This suggests that implantation of a CGS could be a promising treatment for VML wounds.