Forkhead box class O family member proteins (FoxOs) are highly conserved transcription factors with important roles in cellular homeostasis. The four FoxO members in humans, FoxO1, FoxO3, FoxO4, and ...FoxO6, are all expressed in skeletal muscle, but the first three members are the most studied in muscle. In this review, we detail the multiple modes of FoxO regulation and discuss the central role of these proteins in the control of skeletal muscle plasticity. FoxO1 and FoxO3 are key factors of muscle energy homeostasis through the control of glycolytic and lipolytic flux, and mitochondrial metabolism. They are also key regulators of protein breakdown, as they modulate the activity of several actors in the ubiquitin–proteasome and autophagy–lysosomal proteolytic pathways, including mitochondrial autophagy, also called mitophagy. FoxO proteins have also been implicated in the regulation of the cell cycle, apoptosis, and muscle regeneration. Depending of their activation level, FoxO proteins can exhibit ambivalent functions. For example, a basal level of FoxO factors is necessary for cellular homeostasis and these proteins are required for adaptation to exercise. However, exacerbated activation may occur in the course of several diseases, resulting in metabolic disorders and atrophy. A better understanding of the precise functions of these transcriptions factors should thus lead to the development of new therapeutic approaches to prevent or limit the muscle wasting that prevails in numerous pathological states, such as immobilization, denervated conditions, neuromuscular disease, aging, AIDS, cancer, and diabetes.
This study compared the effects of a brief repeated sprint training (RST) intervention performed with bilateral blood flow restriction (BFR) conditions in normoxia or conducted at high levels of ...hypoxia on response to exercise. Thirty-nine endurance-trained athletes completed six repeated sprints cycling sessions spread over 2 weeks consisting of four sets of five sprints (10-s maximal sprints with 20-s active recovery). Athletes were assigned to one of the four groups and subjected to a bilateral partial blood flow restriction (45% of arterial occlusion pressure) of the lower limbs during exercise (BFRG), during the recovery (BFRrG), exercised in a hypoxic room simulating hypoxia at FiO.sub.2 appox. equal to 13% (HG) or were not subjected to additional stress (CG). Peak aerobic power during an incremental test, exercise duration, maximal accumulated oxygen deficit and accumulated oxygen uptake (VO.sub.2) during a supramaximal constant-intensity test were improved thanks to RST (p < 0.05). No significant differences were observed between the groups (p > 0.05). No further effect was found on other variables including time-trial performance and parameters of the force-velocity relationship (p > 0.05). Thus, peak aerobic power, exercise duration, maximal accumulated oxygen deficit, and VO.sub.2 were improved during a supramaximal constant-intensity exercise after six RST sessions. However, combined hypoxic stress or partial BFR did not further increase peak aerobic power.
Physical exercise is a stress that can substantially modulate cellular signaling mechanisms to promote morphological and metabolic adaptations. Skeletal muscle protein and organelle turnover is ...dependent on two major cellular pathways: Forkhead box class O proteins (FOXO) transcription factors that regulate two main proteolytic systems, the ubiquitin-proteasome, and the autophagy-lysosome systems, including mitochondrial autophagy, and the MTORC1 signaling associated with protein translation and autophagy inhibition. In recent years, it has been well documented that both acute and chronic endurance exercise can affect the autophagy pathway. Importantly, substantial efforts have been made to better understand discrepancies in the literature on its modulation during exercise. A single bout of endurance exercise increases autophagic flux when the duration is long enough, and this response is dependent on nutritional status, since autophagic flux markers and mRNA coding for actors involved in mitophagy are more abundant in the fasted state. In contrast, strength and resistance exercises preferentially raise ubiquitin-proteasome system activity and involve several protein synthesis factors, such as the recently characterized DAGK for mechanistic target of rapamycin activation. In this review, we discuss recent progress on the impact of acute and chronic exercise on cell component turnover systems, with particular focus on autophagy, which until now has been relatively overlooked in skeletal muscle. We especially highlight the most recent studies on the factors that can impact its modulation, including the mode of exercise and the nutritional status, and also discuss the current limitations in the literature to encourage further works on this topic.
PURPOSEThe aim of this study was to characterize skeletal muscle protein breakdown and mitochondrial dynamics markers at different points of endurance exercise.
METHODSMice run at 10 m·min during 1 ...h, and running speed was increased by 0.5 m·min every minute during 40 min and then by 1 m·min until exhaustion. Animals were killed by cervical dislocation at 30, 60, 90, and 120 min; at time to exhaustion (Te); and at 3 and 24 h during recovery. The soleus and the deep red regions of the quadriceps muscles were pooled.
RESULTSAMPK phosphorylation (Thr172) increased from 30 min to Te, and FoxO3a phosphorylation (Thr32 and Ser253) decreased from 120 min to 3 h after exercise. FoxO3a-dependent E3 ligases Mul1 and MuRF1 proteins increased from 30 min to Te and at Te and 3 h after exercise, respectively, whereas MAFbx/atrogin-1 protein expression did not change significantly. The autophagic markers LC3B-II increased at 120 min and Te, and p62 significantly decreased at Te. The AMPK-dependent phosphorylation of Ulk1 at Ser317 and Ser555 increased from 60 min to Te and at 30 and 60 min, respectively. Akt (Ser473), MTOR (Ser2448), and 4E-BP1 (Thr37/46) phosphorylation decreased from 90 min to Te, and the MTOR-dependent phosphorylation of Ulk1 (Ser757) decreased from 120 min to Te. Ser616 phosphorylation of the mitochondrial fission marker DRP1 increased from 60 min to Te, but protein expression of the fusion markers mitofusin-2, a substrate of Mul1, and OPA1 did not significantly change.
CONCLUSIONSThese results fit with a regulation of protein breakdown triggered by FoxO3a and Ulk1 pathways after AMPK activation and Akt/MTOR inhibition. Furthermore, our data suggest that mitochondrial fission is quickly increased, and mitochondrial fusion is unchanged during exercise.
The AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that acts as a sensor of cellular energy status switch regulating several systems including glucose and lipid metabolism. ...Recently, AMPK has been implicated in the control of skeletal muscle mass by decreasing mTORC1 activity and increasing protein degradation through regulation of ubiquitin-proteasome and autophagy pathways. In this review, we give an overview of the central role of AMPK in the control of skeletal muscle plasticity. We detail particularly its implication in the control of the hypertrophic and atrophic signaling pathways. In the light of these cumulative and attractive results, AMPK appears as a key player in regulating muscle homeostasis and the modulation of its activity may constitute a therapeutic potential in treating muscle wasting syndromes in humans.
The mTORC1 pathway is required for both the terminal muscle differentiation and hypertrophy by controlling the mammalian translational machinery via phosphorylation of S6K1 and 4E-BP1. mTOR and S6K1 ...are connected by interacting with the eIF3 initiation complex. The regulatory subunit eIF3f plays a major role in muscle hypertrophy and is a key target that accounts for MAFbx function during atrophy. Here we present evidence that in MAFbx-induced atrophy the degradation of eIF3f suppresses S6K1 activation by mTOR, whereas an eIF3f mutant insensitive to MAFbx polyubiquitination maintained persistent phosphorylation of S6K1 and rpS6. During terminal muscle differentiation a conserved TOS motif in eIF3f connects mTOR/raptor complex, which phosphorylates S6K1 and regulates downstream effectors of mTOR and Cap-dependent translation initiation. Thus eIF3f plays a major role for proper activity of mTORC1 to regulate skeletal muscle size.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This study exanimated the effects of intermittent hypoxic training (IHT) conducted at a high level of hypoxia with recovery at ambient air on aerobic/anaerobic capacities at sea level and ...hematological variations. According to a double-blind randomized design, fifteen highly endurance-trained runners completed a 6-weeks regimented training with 3 sessions per week consisting of intermittent runs (6x work-rest ratio of 5ʹ:5ʹ) on a treadmill at 80-85% of maximal aerobic speed (
). Nine athletes (hypoxic group, HG) performed the exercise bouts at FI0
2
= 10.6-11.4% while six athletes (normoxic group, NG) exercised at ambient air. Running time to exhaustion at a velocity corresponding to 95%
significantly increased for HG while no effect was found for NG. Regarding
, no significant effects were found in either training group. In addition, the decline of jumping performances over a 45s-continuous maximal vertical jump test (i.e. anaerobic capacity index) tended to be lower in HG compared to NG. The levels of the studied hematological variables, including erythropoietin and hematocrit, did not significantly change for either HG or NG. These results highlight that our IHT protocol may induce additional effects on aerobic performance without compromising the anaerobic capacity index in highly-trained athletes.
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