Rapamycin administration causes a decrease in muscle contractile function and systemic glucose intolerance concomitant with reduced skeletal muscle Rictor, the mTORC2 component, expression independent of energy intake in young rats.

Emerging evidence suggests the potential of rapamycin, an antibiotic from Streptomyces hygroscopicus that functions as a mechanistic target of rapamycin (mTOR) inhibitor, as a mimetic of caloric restriction (CR) for maintaining skeletal muscle health. Several studies showed that rapamycin administration (RAP) reduced appetite and energy intake. However, the physiological and molecular differences between RAP and CR in skeletal muscle are not fully understood.

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.

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.

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.

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.

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.

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.

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.

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.

The distribution of eukaryotic initiation factor 4E after bouts of resistance exercise is altered by shortening of recovery periods.

Insufficient duration of recovery between resistance exercise bouts reduces the effects of exercise training, but the influence on muscle anabolic responses is not fully understood. Here, we investigated the changes in the distribution of eukaryotic initiation factor (eIF) 4E, a key regulator of translation initiation, and related factors in mouse skeletal muscle after three successive bouts of resistance exercise with three durations of recovery periods (72 h: conventional, 24 h: shorter, and 8 h: excessively shorter). Bouts of resistance exercise dissociated eIF4E from eIF4E binding protein 1, with the magnitude increasing with shorter recovery.

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.

Habitual high-protein diet does not influence muscle protein synthesis in response to acute resistance exercise in rats.

Objectives: Resistance training combined with consumption of a high-protein diet (HPD) is typically recommended to increase muscle mass, as both acute resistance exercise (RE) and dietary protein intake stimulate mechanistic target of rapamycin complex 1 (mTORC1) and muscle protein synthesis (MPS). However, the effect of chronic HPD consumption on MPS response to an acute RE remains to be determined.

Methods: Male Sprague-Dawley rats aged 10 wk were fed HPD (50 kcal % protein, for 4 wk) or normal protein diet (NPD; 20 kcal % protein).

High-intensity muscle contraction-mediated increases in Akt1 and Akt2 phosphorylation do not contribute to mTORC1 activation and muscle protein synthesis.

High-intensity muscle contraction (HiMC) is known to induce muscle protein synthesis, a process in which mechanistic target of rapamycin (mTOR) is reported to play a critical role. However, the mechanistic details have not been completely elucidated. Here, we investigated whether Akt plays a role in regulating HiMC-induced mTORC1 activation and muscle protein synthesis using a rodent model of resistance exercise and MK2206 (an Akt kinase inhibitor).

Influence of shortened recovery between resistance exercise sessions on muscle-hypertrophic effect in rat skeletal muscle.

Resistance exercise training induces muscle hypertrophy, and recovery between sessions is one of the major determinants of this effect. However, the effect of the recovery period between sessions on muscle hypertrophy following resistance exercise training remains unclear. To elucidate the effect of recovery period on hypertrophy, in the present study, we investigated changes in protein degradation systems and hypertrophic responses in rat skeletal muscle to resistance training with variable recovery periods.

The Effect of Changing the Contraction Mode During Resistance Training on mTORC1 Signaling and Muscle Protein Synthesis.

Acute resistance exercise (RE) increases muscle protein synthesis (MPS) via activation of mechanistic target of rapamycin complex (mTORC), and chronic resistance exercise training (RT) results in skeletal muscle hypertrophy. Although MPS in response to RE is blunted over time during RT, no effective restorative strategy has been identified. Since eccentric muscle contraction (EC) has the potential to strongly stimulate mTORC1 activation and MPS, changing the muscle contraction mode to EC might maintain the MPS response to RE during chronic RT.

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.

Chemical denervation using botulinum toxin increases Akt expression and reduces submaximal insulin-stimulated glucose transport in mouse muscle.

Botulinum toxin A (botox) is a toxin used for spasticity treatment and cosmetic purposes. Botox blocks the excitation of skeletal muscle fibers by preventing the release of acetylcholine from motor nerves, a process termed chemical denervation. Surgical denervation is associated with increased expression of the canonical insulin-activated kinase Akt, lower expression of glucose handling proteins GLUT4 and hexokinase II (HKII) and insulin resistant glucose uptake, but it is not known if botox has a similar effect.

Effect of Mixed Meal and Leucine Intake on Plasma Amino Acid Concentrations in Young Men.

Dietary protein intake is critical for the maintenance of skeletal muscle mass. Plasma amino acid concentrations increase with protein intake and increases in muscle protein synthesis are dependent on leucine concentrations. We aimed to investigate the effect of a mixed meal and free amino acids intake on plasma leucine concentrations.

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.

Past injurious exercise attenuates activation of primary calcium-dependent injury pathways in skeletal muscle during subsequent exercise.

Past contraction-induced skeletal muscle injury reduces the degree of subsequent injury; this phenomenon is called the "repeated bout effect (RBE)." This study addresses the mechanisms underlying the RBE, focusing on primary calcium-dependent injury pathways. Wistar rats were subdivided into single injury (SI) and repeated injury (RI) groups.

Electrically evoked local muscle contractions cause an increase in hippocampal BDNF.

High-intensity exercise has recently been shown to cause an increase in brain-derived neurotropic factor (BDNF) in the hippocampus. Some studies have suggested that myokines secreted from contracting skeletal muscle, such as irisin (one of the truncated form of fibronectin type III domain-containing protein 5 (FNDC5)), play important roles in this process. Thus, we hypothesized that locally evoked muscle contractions may cause an increase of BDNF in the hippocampus through some afferent mechanisms.

Relationship between Dietary Protein or Essential Amino Acid Intake and Training-Induced Muscle Hypertrophy among Older Individuals.

Dietary protein intake is critical for maintaining an optimal muscle mass, especially among older individuals. Although protein supplementation during resistance training (RT) has been shown to further augment training-induced muscle mass in older individuals, the impact of daily variations in protein intake on training-induced muscle mass has not been explored thus far. Therefore, this study aimed to investigate the relationship between the dietary protein and amino acid intake and RT-induced muscle hypertrophy among older individuals.

Repeated bouts of resistance exercise with short recovery periods activates mTOR signaling, but not protein synthesis, in mouse skeletal muscle.

The recovery period between bouts of exercise is one of the major factors influencing the effects of resistance exercise, in addition to exercise intensity and volume. However, the effects of shortening the recovery time between bouts of resistance exercise on subsequent protein synthesis remain unclear. In this study, we investigated the consequences of shortening the recovery time between bouts of resistance exercise on protein synthesis and related processes in mouse skeletal muscles.

Effects of contraction mode and stimulation frequency on electrical stimulation-induced skeletal muscle hypertrophy.

We compared the skeletal muscle hypertrophy resulting from isometric (Iso) or eccentric (Ecc) electrical stimulation (ES) training with different stimulation frequencies. Male Wistar rats were assigned to the Iso and Ecc groups. These were divided into three further subgroups that were stimulated at 10 Hz (Iso-10 and Ecc-10), 30 Hz (Iso-30 and Ecc-30), or 100 Hz (Iso-100 and Ecc-100).

Influence of past injurious exercise on fiber type-specific acute anabolic response to resistance exercise in skeletal muscle.

We investigated the influence of past injurious exercise on anabolic response of skeletal muscle fibers to resistance exercise (RE). Wistar rats were divided into exercise (E) and exercise-after-injury (I-E) groups. At age 10 wk, the right gastrocnemius muscle in each rat in the I-E group was subjected to strenuous eccentric contractions.