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The dynamic coordination of processes controlling the quality of the mitochondrial network is crucial to maintain the function of mitochondria in skeletal muscle. Changes of mitochondrial proteolytic system, dynamics (fusion/fission), and mitophagy induce pathways that affect muscle mass and performance. When muscle mass is lost, the risk of disease onset and premature death is dramatically increased. For instance, poor quality of muscles correlates with the onset progression of several age-related disorders such as diabetes, obesity, cancer, and aging sarcopenia. To date, there are no drug therapies to reverse muscle loss, and exercise remains the best approach to improve mitochondrial health and to slow atrophy in several diseases. This review will describe the principal mechanisms that control mitochondrial quality and the pathways that link mitochondrial dysfunction to muscle mass regulation.

Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. Consequently, the growth or the loss of muscle mass can influence general metabolism, locomotion, eating and respiration. Therefore, it is not surprising that excessive muscle loss is a bad prognostic index of a variety of diseases ranging from cancer, organ failure, infections and unhealthy ageing. Muscle function is influenced by different quality systems that regulate the function of contractile proteins and organelles. These systems are controlled by transcriptional dependent programs that adapt muscle cells to environmental and nutritional clues. Mechanical, oxidative, nutritional and energy stresses, as well as growth factors or cytokines modulate signaling pathways that, ultimately, converge on protein and organelle turnover. Novel insights that control and orchestrate such complex network are continuously emerging and will be summarized in this review. Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non-hereditary diseases and for the improvement of the quality of life during ageing. Loss of muscle mass is associated with ageing and with a number of diseases such as cancer. Here, the authors review the signaling pathways that modulate protein synthesis and degradation and gain or loss of muscle mass, and discuss therapeutic implications and future directions for the field.

Skeletal muscle is a plastic organ that is maintained by multiple pathways regulating cell and protein turnover. During muscle atrophy, proteolytic systems are activated, and contractile proteins and organelles are removed, resulting in the shrinkage of muscle fibers. Excessive loss of muscle mass is associated with poor prognosis in several diseases, including myopathies and muscular dystrophies, as well as in systemic disorders such as cancer, diabetes, sepsis and heart failure. Muscle loss also occurs during aging. In this paper, we review the key mechanisms that regulate the turnover of contractile proteins and organelles in muscle tissue, and discuss how impairments in these mechanisms can contribute to muscle atrophy. We also discuss how protein synthesis and degradation are coordinately regulated by signaling pathways that are influenced by mechanical stress, physical activity, and the availability of nutrients and growth factors. Understanding how these pathways regulate muscle mass will provide new therapeutic targets for the prevention and treatment of muscle atrophy in metabolic and neuromuscular diseases.

Abstract withdrawn to prevent dissemination of unpublished results.

Nutrient deprivation and other stress stimuli elicit metabolic changes (such as the induction of autophagy and activation of FOXO transcription factors) that help an organism adapt to stressful conditions. A link between these stress response pathways is revealed by the finding that FOXO3 upregulates the expression of glutamine synthetase to promote glutamine accumulation, inhibit mTOR signalling and promote autophagy.

Stresses like low nutrients, systemic inflammation, cancer or infections provoke a catabolic state characterized by enhanced muscle proteolysis and amino acid release to sustain liver gluconeogenesis and tissue protein synthesis. These conditions activate the family of Forkhead Box (Fox) O transcription factors. Here we report that muscle-specific deletion of FoxO members protects from muscle loss as a result of the role of FoxOs in the induction of autophagy–lysosome and ubiquitin–proteasome systems. Notably, in the setting of low nutrient signalling, we demonstrate that FoxOs are required for Akt activity but not for mTOR signalling. FoxOs control several stress–response pathways such as the unfolded protein response, ROS detoxification, DNA repair and translation. Finally, we identify FoxO-dependent ubiquitin ligases including MUSA1 and a previously uncharacterised ligase termed SMART (Specific of Muscle Atrophy and Regulated by Transcription). Our findings underscore the central function of FoxOs in coordinating a variety of stress-response genes during catabolic conditions. FoxO transcription factors promote muscle atrophy in response to stresses such as low nutrient availability. By generating muscle-specific FoxO triple-knockout mice, Milan et al. identify mechanisms by which the FoxO transcriptional network coordinates autophagic and proteasomal protein degradation.

Mitochondrial quality control is essential in highly structured cells such as neurons and muscles. In skeletal muscle the mitochondrial fission proteins are reduced in different physiopathological conditions including ageing sarcopenia, cancer cachexia and chemotherapy-induced muscle wasting. However, whether mitochondrial fission is essential for muscle homeostasis is still unclear. Here we show that muscle-specific loss of the pro-fission dynamin related protein (DRP) 1 induces muscle wasting and weakness. Constitutive Drp1 ablation in muscles reduces growth and causes animal death while inducible deletion results in atrophy and degeneration. Drp1 deficient mitochondria are morphologically bigger and functionally abnormal. The dysfunctional mitochondria signals to the nucleus to induce the ubiquitin-proteasome system and an Unfolded Protein Response while the change of mitochondrial volume results in an increase of mitochondrial Ca 2+ uptake and myofiber death. Our findings reveal that morphology of mitochondrial network is critical for several biological processes that control nuclear programs and Ca 2+ handling. Muscle loss is associated with altered expression of proteins involved in mitochondrial homeostasis, but whether this is causative remains unclear. Here, the authors show that genetic ablation of the pro-fission protein DRP1 leads to accumulation of abnormal mitochondria that induce muscle atrophy by altering Ca 2+ homeostasis and cellular stress responses.

This study was designed to support the tactical decisions of wheelchair basketball (WB) coaches in identifying the best players to form winning lineups. Data related to a complete regular season of a top-level WB Championship were examined. By analyzing game-related statistics from the first round, two clusters were identified that accounted for approximately 35% of the total variance. Cluster 1 was composed of low-performing athletes, while Cluster 2 was composed of high-performing athletes. Based on data related to the second round of the Championship, we conducted a two-fold evaluation of the clusters identified in the first round with the team’s net performance as the outcome variable. The results showed that teams where players belonging to Cluster 2 had played more time during the second round of the championship were also those with the better team performance (R-squared = 0.48, p = 0.035), while increasing the playing time for players from Classes III and IV does not necessarily improve team performance (r2 = -0.14, p = 0.59). These results of the present study suggest that a collaborative approach between coaches and data scientists would significantly advance this Paralympic sport.

Assessing the scoring probability of teams and players in different areas of a court map is an important topic in basketball analytics, in order to define both game strategies and training programmes. In this contribution we propose a spatial statistical method based on classification trees, aimed to define a partition of the court in rectangles with maximally different shooting performances. Each analyzed team/player is characterized by its/his own partition, so comparisons can be made among different teams/players. In addition, shooting efficiency measures computed within the rectangles can be used to define spatial shooting performance indicators.

Metabolic homeostasis is essential for cellular survival and proper tissue function. Multi-systemic metabolic regulation is therefore vital for good health. A number of tissues have the task of maintaining appropriate metabolism, and skeletal muscle is the most abundant of them. Muscle possesses a remarkable plasticity and is able to rapidly adapt to changes in energetic demands by fine-tuning the balance between catabolic and anabolic processes. Autophagy is a catabolic process responsible for the degradation of protein aggregates and damaged organelles, through the autophagosome–lysosome system. Proper regulation of autophagy flux is fundamental for organism homeostasis under physiological conditions and even more in response to metabolic stress, such as during physical activity and nutritional deficits. Both deficient and excessive autophagy are harmful for health and have devastating consequences in a myriad of pathologies. The regulation of autophagy flux in various tissues, and in particular in skeletal muscle, is of great importance for health and tissue homeostasis and represents a feasible mechanism by which physical exercise exerts its beneficial effects on muscle and whole body metabolism. This review is focused on the key molecular mechanisms regulating macromolecule and organelle turnover in muscle during alterations in nutrient availability and energetic demands, as well as their involvement in disease pathogenesis.