Joaquín Pérez-Schindler

Skeletal muscle PGC-1α controls whole-body lactate homeostasis through estrogen-related receptor α-dependent activation of LDH B and repression of LDH A

The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) controls metabolic adaptations. We now show that PGC-1α in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-α–dependent manner. Concomitantly, PGC-1α reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1α thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1α actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1α–mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health.

The corepressor NCoR1 antagonizes PGC-1α and estrogen-related receptor α in the regulation of skeletal muscle function and oxidative metabolism.

ABSTRACT Skeletal muscle exhibits a high plasticity and accordingly can quickly adapt to different physiological and pathological stimuli by changing its phenotype largely through diverse epigenetic mechanisms. The nuclear receptor corepressor 1 (NCoR1) has the ability to mediate gene repression; however, its role in regulating biological programs in skeletal muscle is still poorly understood. We therefore studied the mechanistic and functional aspects of NCoR1 function in this tissue. NCoR1 muscle-specific knockout mice exhibited a 7.2% higher peak oxygen consumption (VO2peak), a 11% reduction in maximal isometric force, and increased ex vivo fatigue resistance during maximal stimulation. Interestingly, global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) overexpression on oxidative metabolism in muscle. Importantly, PPARβ/δ and estrogen-related receptor α (ERRα) were identified as common targets of NCoR1 and PGC-1α with opposing effects on the transcriptional activity of these nuclear receptors. In fact, the repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1α-mediated coactivation of ERRα. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases.

Skeletal muscle homeostasis and plasticity in youth and ageing: impact of nutrition and exercise

Skeletal muscles comprise a substantial portion of whole body mass and are integral for locomotion and metabolic health. Increasing age is associated with declines in both muscle mass and function (e.g. strength‐related performance, power) with declines in muscle function quantitatively outweighing those in muscle volume. The mechanisms behind these declines are multi‐faceted involving both intrinsic age‐related metabolic dysregulation and environmental influences such as nutritional and physical activity. Ageing is associated with a degree of ‘anabolic resistance’ to these key environmental inputs, which likely accelerates the intrinsic processes driving ageing. On this basis, strategies to sensitize and/or promote anabolic responses to nutrition and physical activity are likely to be imperative in alleviating the progression and trajectory of sarcopenia. Both resistance‐ and aerobic‐type exercises are likely to confer functional and health benefits in older age, and a clutch of research suggests that enhancement of anabolic responsiveness to exercise and/or nutrition may be achieved by optimizing modifications of muscle‐loading paradigms (workload, volume, blood flow restriction) or nutritional support (e.g. essential amino acid/leucine) patterns. Nonetheless, more work is needed in which a more holistic view in ageing studies is taken into account. This should include improved characterization of older study recruits, that is physical activity/nutritional behaviours, to limit confounding variables influencing whether findings are attributable to age, or other environmental influences. Nonetheless, on balance, ageing is associated with declines in muscle mass and function and a partially related decline in aerobic capacity. There is also good evidence that metabolic flexibility is impaired in older age.

The transcriptional coactivator PGC-1α is dispensable for chronic overload-induced skeletal muscle hypertrophy and metabolic remodeling

Significance Skeletal muscle hypertrophy is mainly induced by growth hormones and mechanical overload and exerts health beneficial effects. The mammalian target of rapamycin complex 1 (mTORC1) and the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) are key regulators of skeletal muscle mass and energy metabolism, respectively. Thus, acting in concert, mTORC1 and PGC-1α interplay is thought to regulate skeletal muscle function. Our results indicate that PGC-1α is not required for skeletal muscle hypertrophy and a slow-contractile phenotype induced by chronic overload of the plantaris muscle. In fact, PGC-1α gene expression and global energy metabolism were repressed in this experimental context of muscle hypertrophy. Hence, these results exclude PGC-1α as the main regulator of skeletal muscle remodeling after chronic overload. Skeletal muscle mass loss and dysfunction have been linked to many diseases. Conversely, resistance exercise, mainly by activating mammalian target of rapamycin complex 1 (mTORC1), promotes skeletal muscle hypertrophy and exerts several therapeutic effects. Moreover, mTORC1, along with peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), regulates skeletal muscle metabolism. However, it is unclear whether PGC-1α is required for skeletal muscle adaptations after overload. Here we show that although chronic overload of skeletal muscle via synergist ablation (SA) strongly induces hypertrophy and a switch toward a slow-contractile phenotype, these effects were independent of PGC-1α. In fact, SA down-regulated PGC-1α expression and led to a repression of energy metabolism. Interestingly, however, PGC-1α deletion preserved peak force after SA. Taken together, our data suggest that PGC-1α is not involved in skeletal muscle remodeling induced by SA.

Rapamycin does not prevent increases in myofibrillar or mitochondrial protein synthesis following endurance exercise

Previous studies have shown that endurance exercise increases myofibrillar (MyoPS) and mitochondrial (MitoPS) protein synthesis in skeletal muscle. The mechanistic target of rapamycin (mTOR) is considered to be a key intracellular nutrient‐sensing protein complex, which activates MyoPS in response to anabolic stimuli. Little is known regarding the regulation of MyoPS and MitoPS in response to endurance exercise. In the present study, we show that MyoPS and MitoPS increase in skeletal muscle following endurance exercise, despite suppression of mTORC1 during the post‐exercise recovery period. Our data suggests that mTORC1 independent processes regulate both MyoPS and MitoPS following acute endurance exercise.

Understanding the acetylome: translating targeted proteomics into meaningful physiology

It is well established that exercise elicits a finely tuned adaptive response in skeletal muscle, with contraction frequency, duration, and recovery shaping skeletal muscle plasticity. Given the power of physical activity to regulate metabolic health, numerous research groups have focused on the molecular mechanisms that sense, interpret, and translate this contractile signal into postexercise adaptation. While our current understanding is that contraction-sensitive allosteric factors (e.g., Ca2+, AMP, NAD+, and acetyl-CoA) initiate signaling changes, how the muscle translates changes in these factors into the appropriate adaptive response remains poorly understood. During the past decade, systems biology approaches, utilizing “omics” screening techniques, have allowed researchers to define global processes of regulation with incredible sensitivity and specificity. As a result, physiologists are now able to study substrate flux with stable isotope tracers in combination with metabolomic approaches and to coordinate these functional changes with proteomic and transcriptomic analysis. In this review, we highlight lysine acetylation as an important posttranslational modification in skeletal muscle. We discuss the evolution of acetylation research and detail how large proteomic screens in diverse metabolic systems have led to the current hypothesis that acetylation may be a fundamental mechanism to fine-tune metabolic adaptation in skeletal muscle.

Nutritional strategies to support concurrent training

Abstract Concurrent training (the combination of endurance exercise to resistance training) is a common practice for athletes looking to maximise strength and endurance. Over 20 years ago, it was first observed that performing endurance exercise after resistance exercise could have detrimental effects on strength gains. At the cellular level, specific protein candidates have been suggested to mediate this training interference; however, at present, the physiological reason(s) behind the concurrent training effect remain largely unknown. Even less is known regarding the optimal nutritional strategies to support concurrent training and whether unique nutritional approaches are needed to support endurance and resistance exercise during concurrent training approaches. In this review, we will discuss the importance of protein supplementation for both endurance and resistance training adaptation and highlight additional nutritional strategies that may support concurrent training. Finally, we will attempt to synergise current understanding of the interaction between physiological responses and nutritional approaches into practical recommendations for concurrent training.

Pathophysiological relevance of the cardiac β2-adrenergic receptor and its potential as a therapeutic target to improve cardiac function.

β-adrenoceptors are members of the G protein-coupled receptor superfamily which play a key role in the regulation of myocardial function. Their activation increases cardiac performance but can also induce deleterious effects such as cardiac arrhythmias or myocardial apoptosis. In fact, inhibition of β-adrenoceptors exerts a protective effect in patients with sympathetic over-stimulation during heart failure. Although β(2)-adrenoceptor is not the predominant subtype in the heart, it seems to importantly contribute to the cardiac effects of adrenergic stimulation; however, the mechanism by which this occurs is not fully understood. This review summarizes the current knowledge on the role of β(2)-adrenoceptors in the regulation of cardiac contractility, metabolism, cardiomyocyte survival and cardiac arrhythmias. In addition, therapeutic considerations relating to stimulation of the β(2)-adrenoceptor such as an increase in cardiac contractility with low arrythmogenic effect, protection of the myocardium again apoptosis or positive regulation of heart metabolism are discussed.

The coactivator PGC-1α regulates skeletal muscle oxidative metabolism independently of the nuclear receptor PPARβ/δ in sedentary mice fed a regular chow diet

Aims/hypothesisPhysical activity improves oxidative capacity and exerts therapeutic beneficial effects, particularly in the context of metabolic diseases. The peroxisome proliferator-activated receptor (PPAR) γ coactivator-1α (PGC-1α) and the nuclear receptor PPARβ/δ have both been independently discovered to play a pivotal role in the regulation of oxidative metabolism in skeletal muscle, though their interdependence remains unclear. Hence, our aim was to determine the functional interaction between these two factors in mouse skeletal muscle in vivo.MethodsAdult male control mice, PGC-1α muscle-specific transgenic (mTg) mice, PPARβ/δ muscle-specific knockout (mKO) mice and the combination PPARβ/δ mKO + PGC-1α mTg mice were studied under basal conditions and following PPARβ/δ agonist administration and acute exercise. Whole-body metabolism was assessed by indirect calorimetry and blood analysis, while magnetic resonance was used to measure body composition. Quantitative PCR and western blot were used to determine gene expression and intracellular signalling. The proportion of oxidative muscle fibre was determined by NADH staining.ResultsAgonist-induced PPARβ/δ activation was only disrupted by PPARβ/δ knockout. We also found that the disruption of the PGC-1α–PPARβ/δ axis did not affect whole-body metabolism under basal conditions. As expected, PGC-1α mTg mice exhibited higher exercise performance, peak oxygen consumption and lower blood lactate levels following exercise, though PPARβ/δ mKO + PGC-1α mTg mice showed a similar phenotype. Similarly, we found that PPARβ/δ was dispensable for PGC-1α-mediated enhancement of an oxidative phenotype in skeletal muscle.Conclusions/interpretationCollectively, these results indicate that PPARβ/δ is not an essential partner of PGC-1α in the control of skeletal muscle energy metabolism.

Variability in the magnitude of response of metabolic enzymes reveals patterns of co-ordinated expression following endurance training in women.

Skeletal muscles improve their oxidative fatty acid and glucose metabolism following endurance training, but the magnitude of response varies considerably from person to person. In 20 untrained young women we examined interindividual variability in training responses of metabolic enzymes following 6 weeks of endurance training, sufficient to increase maximal oxygen uptake by 10 ± 8% (mean ± SD). Training led to increases in mitochondrial enzymes [succinate dehydrogenase (SDH; 47 ± 78%), cytochrome c oxidase (52 ± 70%) and ATP synthase (63 ± 69%)] and proteins involved in fatty acid metabolism [3‐hydroxyacyl CoA dehydrogenase (69 ± 92%) and fatty acid transporter CD36 (86 ± 31%)]. Increases in enzymes of glucose metabolism [phosphofructokinase (29 ± 94%) and glucose transporter 4 (18 ± 65%)] were not significant. There was no relationship between changes in maximal oxygen uptake and the changes in the metabolic proteins. Considerable interindividual variability was seen in the magnitude of responses. The response of each enzyme was proportional to the change in SDH; individuals with a large increase in SDH also showed high gains in all other enzymes, and vice versa. Peroxisome proliferator‐activated receptor γ coactivator 1α protein content increased after training, but was not correlated with changes in the metabolic proteins. In conclusion, the results revealed co‐ordinated adaptation of several metabolic enzymes following endurance training, despite differences between people in the magnitude of response. Differences between individuals in the magnitude of response might reflect the influence of environmental and genetic factors that govern training adaptations.