Mechanisms of mechanical overload-induced skeletal muscle hypertrophy: current understanding and future directions.

Mechanisms underlying mechanical overload-induced skeletal muscle hypertrophy have been extensively researched since the landmark report by Morpurgo (1897) of "work-induced hypertrophy" in dogs that were treadmill trained. Much of the preclinical rodent and human resistance training research to date supports that involved mechanisms include enhanced mammalian/mechanistic target of rapamycin complex 1 (mTORC1) signaling, an expansion in translational capacity through ribosome biogenesis, increased satellite cell abundance and myonuclear accretion, and postexercise elevations in muscle protein synthesis rates. However, several lines of past and emerging evidence suggest that additional mechanisms that feed into or are independent of these processes are also involved. This review first provides a historical account of how mechanistic research into skeletal muscle hypertrophy has progressed. A comprehensive list of mechanisms associated with skeletal muscle hypertrophy is then outlined, and areas of disagreement involving these mechanisms are presented. Finally, future research directions involving many of the discussed mechanisms are proposed.

Implication of satellite cell behaviors in capillary growth via VEGF expression-independent mechanism in response to mechanical loading in HeyL-null mice.

Angiogenesis and muscle satellite cell (SC)-mediated myonuclear accretion are considered essential for the robust response of contraction-induced muscle hypertrophy. Moreover, both myonucleus and SCs are physically adjacent to capillaries and are the major sites for the expression of proangiogenic factors, such as VEGF, in the skeletal muscle. Thus, events involving the addition of new myonuclei via activation of SCs may play an important role in angiogenesis during muscle hypertrophy. However, the relevance among myonuclei number, capillary supply, and angiogenesis factor is not demonstrated. The Notch effector HeyL is specifically expressed in SCs in the skeletal muscle and is crucial for SC proliferation by inhibiting MyoD in overload-induced muscle hypertrophy. Here, we tested whether the addition of new myonuclei by SC in overloaded muscle is associated with angiogenic adaptation by reanalyzing skeletal muscle from HeyL-knockout (KO) mice, which show blunted responses of SC proliferation, myonucleus addition, and overload-induced muscle hypertrophy. Reanalysis confirmed blunted SC proliferation and myonuclear accretion in the plantaris muscle of HeyL-KO mice 9 wk after synergist ablation. Interestingly, the increase in capillary-to-fiber ratio observed in wild-type (WT) mice was impaired in HeyL-KO mice. In both WT and HeyL-KO mice, the expression of VEGFA and VEGFB was similarly increased in response to overload. In addition, the expression pattern of TSP-1, a negative regulator of angiogenesis, was also not changed between WT and HeyL-KO mice. Collectively, these results suggest that SCs activation-myonuclear accretion plays a crucial role in angiogenesis during overload-induced muscle hypertrophy via independent of angiogenesis regulators.

c-Myc overexpression increases ribosome biogenesis and protein synthesis independent of mTORC1 activation in mouse skeletal muscle.

High-intensity muscle contractions (HiMCs) are known to increase c-Myc expression that is known to stimulate ribosome biogenesis and protein synthesis in most cells. However, although c-Myc mRNA transcription and c-Myc mRNA translation have been shown to be upregulated following resistance exercise concomitantly with increased ribosome biogenesis, this connection has not been tested directly. We investigated the effect of adeno-associated virus (AAV)-mediated c-Myc overexpression, with or without fasting or percutaneous electrical stimulation-induced HiMC, on ribosome biogenesis and protein synthesis in adult mouse skeletal muscles. AAV-mediated overexpression of c-Myc in mouse skeletal muscles for 2 wk increased the DNA polymerase subunit POL1 mRNA, 45S-pre-rRNA, total RNA, and muscle protein synthesis without altering mechanistic target of rapamycin complex 1 (mTORC1) signaling under both ad libitum and fasted conditions. RNA-sequencing (RNA-seq) analyses revealed that c-Myc overexpression mainly regulated ribosome biogenesis-related biological processes. The protein synthesis response to c-Myc overexpression mirrored the response with HiMC. No additional effect of combining c-Myc overexpression and HiMC was observed. Our results suggest that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1. Therefore, the HiMC-induced increase in c-Myc may contribute to ribosome biogenesis and increased protein synthesis following HiMC.NEW & NOTEWORTHY Resistance exercise is known to increase c-Myc expression, which is known to stimulate ribosome biogenesis and protein synthesis in a variety of cells. However, whether the increase in c-Myc stimulates ribosome biogenesis and protein synthesis in skeletal muscles remains unknown. We found that c-Myc overexpression is sufficient to stimulate skeletal muscle ribosome biogenesis and protein synthesis without activation of mTORC1.

The relationship between myonuclear number and protein synthesis in individual rat skeletal muscle fibres.

Skeletal muscle has numerous nuclei within a cell. The nucleus is considered as the central organelle for muscle protein synthesis (MPS). However, it is unclear whether myonuclear number is associated with MPS capacity within the individual muscle fibres. Therefore, the purpose of the present study was to reveal the relationship between myonuclear number per unit muscle fibre length and MPS under basal and conditions of elevated MPS by high-intensity muscle contraction (HiMC) using an in vivo nascent protein labelling technique (SUnSET) in rodents. We found that myonuclear number was positively correlated with MPS in individual muscle fibres in the basal condition. Similarly, ribosomal protein S6 (rpS6) content, which is a rough estimate of ribosome content, was positively correlated with MPS. However, myonuclear number was not associated with rpS6 content. In contrast to the basal condition, when MPS was increased by acute HiMC, no correlation was observed between myonuclear number and MPS, but the association between rpS6 and MPS was maintained. Importantly, these observations indicate that the number of nuclei in individual myofibers is related only to MPS at rest. However, the ribosome content in individual fibres is related to MPS of individual myofibers both at rest and following HiMC.

Rapamycin and mTORC2 inhibition synergistically reduce contraction-stimulated muscle protein synthesis.

KEY POINTS: Muscle contractions increase protein synthesis in a mechanistic target of rapamycin (mTOR)-dependent manner, yet it is unclear which/how mTOR complexes regulate muscle protein synthesis. We investigated the requirement of mTOR Complex 2 (mTORC2) in contraction-stimulated muscle protein synthesis. mTORC2 inhibition by muscle-specific Rictor knockout (Rictor mKO) did not prevent contraction-induced muscle protein synthesis. Rapamycin prevented contraction-induced muscle protein synthesis in Rictor mKO but not wild-type mice. ABSTRACT: Protein synthesis increases following muscle contractions. Previous studies have shown that inhibition of the mechanistic target of rapamycin complex 1 (mTORC1) suppresses the early but not late muscle protein synthesis response, while inhibition of both mTORC1 and mTORC2 abolishes the two effects. Therefore, we hypothesized that mTORC2 regulates muscle protein synthesis following muscle contractions. To test this, we investigated the effect of mTORC2 inhibition by mouse muscle-specific Rictor knockout (Rictor mKO) on muscle protein synthesis 3 h after contraction. The right gastrocnemius muscles of Rictor mKO and wild-type (WT) mice were isometrically contracted using percutaneous electrical stimulation, while the left gastrocnemius muscles served as controls. Vehicle or the mTORC1 inhibitor rapamycin (1.5 mg/kg) was injected intraperitoneally 1 h before contraction. Treatment of WT mice with rapamycin and Rictor mKO lowered protein synthesis in general, but the response to contractions was intact 3 h after contractions in both conditions. Rapamycin treatment in Rictor mKO mice prevented contraction-stimulated muscle protein synthesis. Notably, signalling traditionally associated with mTORC1 was increased by muscle contractions despite rapamycin treatment. In rapamycin-treated Rictor mKO mice, the same mTORC1 signalling was blocked following contractions. Our results indicate that although neither rapamycin-sensitive mTOR/mTORC1 nor mTORC2 is necessary for contraction-induced muscle protein synthesis, combined inhibition of rapamycin-sensitive mTOR/mTORC1 and mTORC2 synergistically inhibits contraction-induced muscle protein synthesis.

Rapamycin-insensitive mechanistic target of rapamycin regulates basal and resistance exercise-induced muscle protein synthesis.

We investigated whether rapamycin-insensitive mechanistic target of rapamycin (mTOR) signaling plays a role in regulating resistance exercise-induced muscle protein synthesis. We used a rodent model of resistance exercise and compared the effect of rapamycin, an allosteric mTOR inhibitor, with the effect of AZD8055, an ATP-competitive mTOR kinase inhibitor. The right gastrocnemius muscle of male Sprague-Dawley rats age 11 wk was contracted isometrically via percutaneous electrical stimulation (100 Hz, 5 sets of ten 3-s contractions, 7 s of rest between contractions, 3 min of rest between sets), and the left gastrocnemius muscle served as control. Vehicle, rapamycin, or AZD8055 were intraperitoneally injected 1 h before resistance exercise. Results indicated that both rapamycin and AZD8055 inhibited mTOR complex 1 (mTORC1)/70-kDa ribosomal protein S6 kinase signaling similarly, whereas mTORC1/eukaryotic translation initiation factor 4E-binding protein 1 signaling was greatly inhibited by AZD8055. Moreover, only AZD8055 inhibited the phosphorylation of Akt at Ser473, a downstream target of mTORC2. AZD8055, but not rapamycin, completely inhibited the resistance exercise-induced increase in muscle protein synthesis. We conclude that the resistance exercise-induced increase in muscle protein synthesis is an mTOR signaling-dependent process. Furthermore, both rapamycin-sensitive and -insensitive mTOR signaling regulate this event.-Ogasawara, R., Suginohara, T. Rapamycin-insensitive mechanistic target of rapamycin regulates basal and resistance exercise-induced muscle protein synthesis.

Resistance Exercise-Induced Hypertrophy: A Potential Role for Rapamycin-Insensitive mTOR.

The mechanistic target of rapamycin (mTOR) exerts both rapamycin-sensitive and rapamycin-insensitive signaling events, and the rapamycin-sensitive components of mTOR signaling have been widely implicated in the pathway through which resistance exercise induces skeletal muscle hypertrophy. This review explores the hypothesis that rapamycin-insensitive components of mTOR signaling also contribute to this highly important process.

MicroRNA expression profiling in skeletal muscle reveals different regulatory patterns in high and low responders to resistance training.

Large variability exists in muscle adaptive response to resistance exercise (RE) training between individuals. Recent studies have revealed a significant role for microRNAs (miRNAs) in skeletal muscle plasticity. In this study, we investigated how RE affects miRNA expression and whether the variability of muscle hypertrophy to RE training may be attributed to differential miRNA regulation in the skeletal muscle. To screen high and low responders to RE, we had 18 young men perform arm curl exercise training. After screening, all the men performed 12 wk of lower body RE training, but only the high or low responders participated in the acute RE test before training. Muscle biopsies were obtained from the vastus lateralis muscle at baseline, 3 h after acute RE, and after the training period. Total RNA was extracted from the skeletal muscle, and miRNA expression (800 miRNAs) was analyzed. RE training increased the cross-sectional area of the biceps brachii (-1.7-26.1%), quadriceps (2.2-16.8%), and hamstrings (1.6-18.4%). Eighty-five and 102 miRNAs were differentially expressed after acute and chronic RE, respectively (P < 0.05). Seventeen miRNAs, especially 23b-3p, 26a-5p, 32-5p, 148b-3p, and 376a-3p, were differentially expressed at baseline, and 23 miRNAs, especially let-7a-5p, 95, 148a-3p, and 376a-3p, and 26 miRNAs, especially 30d-5p and 376a-3p, were differentially regulated after acute and chronic RE, respectively, in the skeletal muscle between high and low responders, indicating that the expression patterns of several miRNAs are altered by acute or chronic RE, and that miRNAs are involved in skeletal muscle adaptation to RE training.

Regional adaptation of collagen in skeletal muscle to repeated bouts of strenuous eccentric exercise.

This study investigated the injured region-specific alterations of factors related to the "repeated bout effect" (RBE), i.e., when the first bout of eccentric exercise generates resistance to injuries from the second bout of the same exercise. Wistar rats were divided into single injury (SI) and repeated injury (RI) groups. The right gastrocnemius muscle was subjected to a bout of eccentric contractions (ECs) at the age of 14 weeks in the SI group and 10 and 14 weeks in the RI group. The number of injured fibers after the last bout of ECs was lower in RI than in SI. In the SI group, injured fibers after ECs were mainly located in the superficial region of muscle and expressed myosin heavy chain (MHC) IIx and IIb. Prior to the second bout of ECs, the fiber-type composition in the RI group showed decreased MHC IIx and IIb fibers and increased MHC IIa fibers compared with those in the SI group. However, most regenerating fibers showed either MHC IIx or IIb expression. Heat shock protein 72 and total collagen contents in whole muscle were higher in the RI group than in the SI group; however, only the collagen expression in the RI group was more intense than that in the SI group in the superficial region of muscle. These findings suggest that increased collagen may play a more important role in the injured region of muscle than the other factors in RBE.

Acute bout of resistance exercise increases vitamin D receptor protein expression in rat skeletal muscle.

NEW FINDINGS: What is the central question of this study? Does an acute bout of exercise alter vitamin D receptor expression in rat skeletal muscle? What is the main finding and its importance? Resistance exercise but not endurance exercise increased intramuscular vitamin D receptor expression. Thus, resistance exercise may be an effective way to increase muscle vitamin D receptor expression. Vitamin D and vitamin D receptor (VDR) are involved in the maintenance of skeletal muscle mass and function. Although resistance exercise is well known to enhance muscle growth and improve muscle function, the effect of resistance exercise on VDR has been unclear. We investigated intramuscular VDR expression in response to an acute bout of resistance exercise or endurance exercise. Male adult Sprague-Dawley rats were subjected to either resistance exercise (isometrically exercised via percutaneous electrical stimulation for five sets of ten 3 s contractions, with a 7 s interval between contractions and 3 min rest intervals between sets) or endurance exercise (treadmill at 25 m min(-1) for 60 min). Rats were killed immediately or 1, 3, 6 or 24 h after completion of the resistance or endurance exercise, and gastrocnemius muscles were removed. Non-exercised control animals were killed in a basal state (control group). Intramuscular VDR expression was significantly higher immediately after resistance exercise and elevated for 3 h after exercise compared with the control group (P < 0.05), and the resistance exercise significantly increased phosphorylated ERK1/2 and Mnk1 expression (P < 0.05), which may be associated with VDR expression, immediately after exercise. Additionally, intramuscular expression of cytochrome P450 27B1, an enzyme related to vitamin D metabolism, was significantly higher at 1 and 3 h after exercise (P < 0.05) compared with the control group. In contrast, endurance exercise had no effect on any of the measured proteins. Our results indicate that resistance exercise may be an efficient way to increase intramuscular VDR and related enzyme expression.

The order of concurrent endurance and resistance exercise modifies mTOR signaling and protein synthesis in rat skeletal muscle.

Concurrent training, a combination of endurance (EE) and resistance exercise (RE) performed in succession, may compromise the muscle hypertrophic adaptations induced by RE alone. However, little is known about the molecular signaling interactions underlying the changes in skeletal muscle adaptation during concurrent training. Here, we used an animal model to investigate whether EE before or after RE affects the molecular signaling associated with muscle protein synthesis, specifically the interaction between RE-induced mammalian target of rapamycin complex 1 (mTORC1) signaling and EE-induced AMP-activated protein kinase (AMPK) signaling. Male Sprague-Dawley rats were divided into five groups: an EE group (treadmill, 25 m/min, 60 min), an RE group (maximum isometric contraction via percutaneous electrical stimulation for 3 × 10 s, 5 sets), an EE before RE group, an EE after RE group, and a nonexercise control group. Phosphorylation of p70S6K, a marker of mTORC1 activity, was significantly increased 3 h after RE in both the EE before RE and EE after RE groups, but the increase was smaller in latter. Furthermore, protein synthesis was greatly increased 6 h after RE in the EE before RE group. Increases in the phosphorylation of AMPK and Raptor were observed only in the EE after RE group. Akt and mTOR phosphorylation were increased in both groups, with no between-group differences. Our results suggest that the last bout of exercise dictates the molecular responses and that mTORC1 signaling induced by any prior bout of RE may be downregulated by a subsequent bout of EE.

Ursolic acid stimulates mTORC1 signaling after resistance exercise in rat skeletal muscle.

A recent study identified ursolic acid (UA) as a potent stimulator of muscle protein anabolism via PI3K/Akt signaling, thereby suggesting that UA can increase Akt-independent mTOR complex 1 (mTORC1) activation induced by resistance exercise via Akt signaling. The purpose of the present study was to investigate the effect of UA on resistance exercise-induced mTORC1 activation. The right gastrocnemius muscle of male Sprague-Dawley rats aged 11 wk was isometrically exercised via percutaneous electrical stimulation (stimulating ten 3-s contractions per set for 5 sets), while the left gastrocnemius muscle served as the control. UA or placebo (PLA; corn oil only) was injected intraperitoneally immediately after exercise. The rats were killed 1 or 6 h after the completion of exercise and the target tissues removed immediately. With placebo injection, the phosphorylation of p70(S6K) at Thr(389) increased 1 h after resistance exercise but attenuated to the control levels 6 h after the exercise. On the other hand, the augmented phosphorylation of p70(S6K) was maintained even 6 h after exercise when UA was injected immediately after exercise. A similar trend of prolonged phosphorylation was observed in PRAS40 Thr(246), whereas UA alone or resistance exercise alone did not alter its phosphorylation level at 6 h after intervention. These results indicate that UA is able to sustain resistance exercise-induced mTORC1 activity.

Comparison of muscle hypertrophy following 6-month of continuous and periodic strength training.

To compare the effects of a periodic resistance training (PTR) program with those of a continuous resistance training (CTR) program on muscle size and function, 14 young men were randomly divided into a CTR group and a PTR group. Both groups performed high-intensity bench press exercise training [75 % of one repetition maximum (1-RM); 3 sets of 10 reps] for 3 days per week. The CTR group trained continuously over a 24-week period, whereas the PTR group performed three cycles of 6-week training (or retraining), with 3-week detraining periods between training cycles. After an initial 6 weeks of training, increases in cross-sectional area (CSA) of the triceps brachii and pectoralis major muscles and maximum isometric voluntary contraction of the elbow extensors and 1-RM were similar between the two groups. In the CTR group, muscle CSA and strength gradually increased during the initial 6 weeks of training. However, the rate of increase in muscle CSA and 1-RM decreased gradually after that. In the PTR group, increase in muscle CSA and strength during the first 3-week detraining/6-week retraining cycle were similar to that in the CTR group during the corresponding period. However, increase in muscle CSA and strength during the second 3-week detraining/6-week retraining cycle were significantly higher in the PTR group than in the CTR group. Thus, overall improvements in muscle CSA and strength were similar between the groups. The results indicate that 3-week detraining/6-week retraining cycles result in muscle hypertrophy similar to that occurring with continuous resistance training after 24 weeks.

Effects of high-intensity and blood flow-restricted low-intensity resistance training on carotid arterial compliance: role of blood pressure during training sessions.

We examined the effects of high-intensity resistance training (HIT) and low-intensity blood flow-restricted (LI-BFR) resistance training on carotid arterial compliance. Nineteen young men were randomly divided into HIT (n = 9) or LI-BFR (n = 10) groups. The HIT and LI-BFR groups performed 75 and 30 %, respectively, of one-repetition maximum (1-RM) bench press exercise, 3 days per week for 6 weeks. During the training sessions, the LI-BFR group wore elastic cuffs around the most proximal region of both arms. Muscle cross-sectional area (CSA), 1-RM strength, and carotid arterial compliance were measured before and 3 days after the final training session. Acute changes in systolic arterial pressure (SAP), plasma endothelin-1 (ET-1), nitrite/nitrate (NOx), and noradrenalin concentrations were also measured during and after a bout of training session. The training led to significant increases (P < 0.01) in bench press 1-RM and arm and chest muscle CSA in the two training groups. Carotid arterial compliance decreased significantly (P < 0.05) in the HIT group, but not in the LI-BFR group. There was a significant correlation (r = -0.533, P < 0.05) between the change in carotid arterial compliance and the acute change in SAP during training sessions; however, ET-1 and NOx did not correlate with carotid arterial compliance. Our results suggest that muscle CSA and strength increased following 6 weeks of both HIT and LI-BFR training. However, carotid arterial compliance decreased in only the HIT group, and the changes were correlated with SAP elevations during exercise sessions.

Aging Is Associated With Impaired Postprandial Response of Skeletal Muscle Protein Synthesis to High-Intensity Muscle Contraction in Mice.

The purpose of this study was to investigate whether aging alters the effect of nutritional status on contraction-induced muscle protein metabolism. In an overnight fasted or fed states, the right gastrocnemius muscle of young (3 months) and aged (24 months) male C57BL/6J mice was isometrically contracted via percutaneous electrical stimulation. The left gastrocnemius muscle served as a control. In the fasted state, there were no differences in basal or contraction-induced muscle protein synthesis between young and old mice. However, in the fed state, basal muscle protein synthesis was greater in young mice, and contraction increased muscle protein synthesis only in young mice. In the fed state, although phosphorylation of 4E-BP1 was similarly increased by contraction in both ages, the increase in phosphorylation of p70S6K was greater in young mice. Our results indicate that aging impairs the ability to integrate signals from muscle contraction and nutrition, leading to aging-induced anabolic resistance to muscle contraction in the postprandial state.

Combined effects of low-intensity blood flow restriction training and high-intensity resistance training on muscle strength and size.

We investigated the combined effect of low-intensity blood flow restriction and high-intensity resistance training on muscle adaptation. Forty young men (aged 22-32 years) were randomly divided into four groups of ten subjects each: high-intensity resistance training (HI-RT, 75% of one repetition maximum [1-RM]), low-intensity resistance training with blood flow restriction (LI-BFR, 30% 1-RM), combined HI-RT and LI-BFR (CB-RT, twice-weekly LI-BFR and once-weekly HI-RT), and nontraining control (CON). Three training groups performed bench press exercises 3 days/week for 6 weeks. During LI-BFR training sessions, subjects wore pressure cuffs on both arms that were inflated to 100-160 mmHg. Increases in 1-RM were similar in the HI-RT (19.9%) and CB-RT (15.3%) groups and lower in the LI-BFR group (8.7%, p < 0.05). Maximal isometric elbow extension (MVC) increased in the HI-RT (11.3%) and CB-RT (6.6%) groups; there was no change in the LI-BFR group (-0.2%). The cross-sectional area (CSA) of the triceps brachii (TB) increased (p < 0.05) in the HI-RT (8.6%), CB-RT (7.2%), and LI-BFR (4.4%) groups. The change in relative isometric strength (MVC divided by TB CSA) was greater (p < 0.05) in the HI-RT group (3.3%) than in the LI-BFR (-3.5%) and CON (-0.1%) groups. Following training, relative dynamic strength (1-RM divided by TB CSA) was increased (p < 0.05) by 10.5% in the HI-RT group and 6.7% in the CB-RT group. None of the variables in the CON group changed. Our results show that low-intensity resistance training with BFR-induced functional muscle adaptations is improved by combining it with HI-RT.

Effect of 2-deoxyglucose-mediated inhibition of glycolysis on the regulation of mTOR signaling and protein synthesis before and after high-intensity muscle contraction.

BACKGROUND: Glycolysis controls mTORC1 signaling and protein synthesis. In skeletal muscle, glucose metabolism increases with both exercise/contraction intensity and volume, and therefore, high-intensity muscle contraction (HiMC) such as resistance exercise facilitates glycolysis including glucose uptake and glycogen breakdown. However, it is unknown whether glycolysis regulates HiMC-induced mTORC1 activation and increase in protein synthesis. METHODS: To determine whether glycolysis regulates basal and HiMC-induced mTORC1 signaling and protein synthesis, we employed 2-deoxyglucose (2-DG) to inhibit glycolysis and isometrically contracted the gastrocnemius muscle of Sprague Dawley rats using percutaneous electrical stimulation. RESULTS: Inhibition of glycolysis by 2-DG inhibited basal phosphorylation of p70S6K and 4E-BP1 (downstream targets of mTORC1) and protein synthesis (all P < 0.05) independent of AMPK phosphorylation. AMPK phosphorylation was comparably increased after HiMC at 0 h post HiMC and returned to basal levels 6 h post HiMC in both vehicle- and 2-DG-treated groups. Glycolysis inhibition attenuated muscle contraction-induced phosphorylation of 4E-BP1 at 6 h post HiMC (P < 0.05) but not p70S6K phosphorylation and protein synthesis. CONCLUSION: Although glycolysis is involved in basal but not HiMC-induced muscle protein synthesis, it regulates both basal and HiMC-induced mTORC1 signaling, and may play key roles in skeletal muscle adaptation to HiMC.

Short-term high-fat diet induces muscle fiber type-selective anabolic resistance to resistance exercise.

Chronic obesity and insulin resistance are considered to inhibit contraction-induced muscle hypertrophy, through impairment of mammalian target of rapamycin complex 1 (mTORC1) and muscle protein synthesis (MPS). A high-fat diet is known to rapidly induce obesity and insulin resistance within a month. However, the influence of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute resistance exercise (RE) is unclear. Thus the purpose of this study was to investigate the effect of a short-term high-fat diet on the response of mTORC1 activation and MPS to acute RE. Male Sprague-Dawley rats were randomly assigned to groups and fed a normal diet, high-fat diet, or pair feed for 4 wk. After dietary habituation, acute RE was performed on the gastrocnemius muscle via percutaneous electrical stimulation. The results showed that 4 wk of a high fat-diet induced intramuscular lipid accumulation and insulin resistance, without affecting basal mTORC1 activity or MPS. The response of RE-induced mTORC1 activation and MPS was not altered by a high-fat diet. On the other hand, analysis of each fiber type demonstrated that response of MPS to an acute RE was disappeared specifically in type I and IIa fiber. These results indicate that a short-term high-fat diet causes anabolic resistance to acute RE, depending on the fiber type.NEW & NOTEWORTHY A high-fat diet is known to rapidly induce obesity, insulin resistance, and anabolic resistance to nutrition within a month. However, the influence of a short-term high-fat diet on the response of muscle protein synthesis to acute resistance exercise is unclear. We observed that a short-term high-fat diet causes obesity, insulin resistance, intramuscular lipid droplet accumulation, and anabolic resistance to resistance exercise specifically in type I and IIa fibers.

Basal and resistance exercise-induced increase in protein synthesis is impaired in skeletal muscle of iron-deficient rats.

OBJECTIVES: We aimed to investigate the effect of iron deficiency on basal- and contraction-induced increases in muscle protein synthesis. METHODS: Four-wk-old male Sprague-Dawley rats were divided into three groups. The rats in two of the three groups had free access to a control diet (AD) or iron-deficient diet (ID) for 4 wk. The rats in the third group (CON) were pair-fed the control diet to the mean intake of the ID group. RESULTS: In comparison with the CON group, the ID group showed significantly lower hematocrit and hemoglobin concentrations, iron-containing protein levels, and total iron content in skeletal muscle, but non-iron-containing protein levels did not show any differences between the groups. Protein synthesis, measured by puromycin-labeled peptides, was lower in the ID group compared with the CON group in both basal- and contraction-stimulated states. The ID diet impaired the activation levels of signaling pathways involved in protein synthesis, such as ribosomal protein S6 and eukaryotic translation initiation factor 4E-binding protein 1. Furthermore, dietary iron deficiency decreased autophagy capacity, but did not affect the ubiquitinated protein content. CONCLUSIONS: These results suggest that severe iron deficiency decreases not only basal but also muscle contraction-induced increases in protein synthesis due to, at least in part, downregulation of the protein synthesis signaling pathway in the skeletal muscle.

Effects of Low-Intensity Cycle Training with Restricted Leg Blood Flow on Thigh Muscle Volume and VO2MAX in Young Men.

Concurrent improvements in aerobic capacity and muscle hypertrophy in response to a single mode of training have not been reported. We examined the effects of low-intensity cycle exercise training with and without blood flow restriction (BFR) on muscle size and maximum oxygen uptake (VO2max). A group of 19 young men (mean age ± SD: 23.0 ± 1.7 years) were allocated randomly into either a BFR-training group (n=9, BFR-training) or a non-BFR control training group (n=10, CON-training), both of which trained 3 days/wk for 8 wk. Training intensity and duration were 40% of VO2max and 15 min for the BFR-training group and 40% of VO2max and 45 min for the CON-training group. MRI-measured thigh and quadriceps muscle cross-sectional area and muscle volume increased by 3.4-5.1% (P < 0.01) and isometric knee extension strength tended to increase by 7.7% (p < 0.10) in the BFR-training group. There was no change in muscle size (~0.6%) and strength (~1.4%) in the CON-training group. Significant improvements in VO2max (6.4%) and exercise time until exhaustion (15.4%) were observed in the BFR-training group (p < 0.05) but not in the CON-training group (-0.1 and 3. 9%, respectively). The results suggest that low-intensity, short-duration cycling exercise combined with BFR improves both muscle hypertrophy and aerobic capacity concurrently in young men. Key pointsConcurrent improvements in aerobic capacity and muscle hypertrophy in response to a single mode of training have not been reported.In the present study, low-intensity (40% of VO2max) cycle training with BFR can elicit concurrent improvement in muscle hypertrophy and aerobic capacity.