Modulation of PGC-1α activity as a treatment for metabolic and muscle-related diseases

Physical inactivity is a predisposing factor for various disease states including obesity, cardiovascular disease, as well as for certain types of cancer. Regular endurance exercise mediates several beneficial effects such as increased energy expenditure and improved skeletal muscle function, and has been suggested as a therapeutic strategy for both metabolic and muscle‐related disorders. "Exercise mimetic" is a collective term for compounds that can pharmacologically activate pathways which are normally induced during skeletal muscle contraction, and that could be used in the treatment of metabolic or muscle related diseases. Two such experimental "exercise mimetics" are AICAR and resveratrol, which have both been extensively studied in the context of metabolic dysfunction and muscle wasting in rodent disease models. These compounds have been postulated to activate AMP‐activated protein kinase (AMPK) and sirtuin 1 (SIRT1), respectively, in skeletal muscle, and to increase the activation of the peroxisome proliferator‐activated receptor γ coactivator 1α (PGC‐1α). PGC‐1α can mediate several metabolic and functional adaptations in skeletal muscle in response to physical exercise and is therefore an interesting target for the development of new "exercise mimetic" drugs

A functional motor unit in the culture dish : co-culture of spinal cord explants and muscle cells

Human primary muscle cells cultured aneurally in monolayer rarely contract spontaneously because, in the absence of a nerve component, cell differentiation is limited and motor neuron stimulation is missing(1). These limitations hamper the in vitro study of many neuromuscular diseases in cultured muscle cells. Importantly, the experimental constraints of monolayered, cultured muscle cells can be overcome by functional innervation of myofibers with spinal cord explants in co-cultures. Here, we show the different steps required to achieve an efficient, proper innervation of human primary muscle cells, leading to complete differentiation and fiber contraction according to the method developed by Askanas(2). To do so, muscle cells are co-cultured with spinal cord explants of rat embryos at ED 13.5, with the dorsal root ganglia still attached to the spinal cord slices. After a few days, the muscle fibers start to contract and eventually become cross-striated through innervation by functional neurites projecting from the spinal cord explants that connecting to the muscle cells. This structure can be maintained for many months, simply by regular exchange of the culture medium. The applications of this invaluable tool are numerous, as it represents a functional model for multidisciplinary analyses of human muscle development and innervation. In fact, a complete de novo neuromuscular junction installation occurs in a culture dish, allowing an easy measurement of many parameters at each step, in a fundamental and physiological context. Just to cite a few examples, genomic and/or proteomic studies can be performed directly on the co-cultures. Furthermore, pre- and post-synaptic effects can be specifically and separately assessed at the neuromuscular junction, because both components come from different species, rat and human, respectively. The nerve-muscle co-culture can also be performed with human muscle cells isolated from patients suffering from muscle or neuromuscu diseases(3), and thus can be used as a screening tool for candidate drugs. Finally, no special equipment but a regular BSL2 facility is needed to reproduce a functional motor unit in a culture dish. This method thus is valuable for both the muscle as well as the neuromuscular research communities for physiological and mechanistic studies of neuromuscular function, in a normal and disease context

Optimized Engagement of Macrophages and Satellite Cells in the Repair and Regeneration of Exercised Muscle

Recurring contraction-relaxation cycles exert a massive mechanical load on muscle fibers. Training adaptation therefore entails the promotion of a series of biological programs aimed at inducing a better stress response but also at optimizing repair processes. Muscle regeneration is controlled by an intricate, tightly coordinated engagement of muscle fibers, satellite cells, macrophages and other cell types. In this review, we discuss some of the recent insights into the regulation of muscle repair and regeneration in exercised muscle, elucidate the role of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in this context, and speculate about potential implications for the treatment of muscle diseases

Drugs, clocks and exercise in ageing: hype and hope, fact and fiction

Ageing is a biological process that is linked to a functional decline, ultimately resulting in death. Large interindividual differences exist in terms of life- and healthspan, representing life expectancy and the number of years spent in the absence of major diseases, respectively. The genetic and molecular mechanisms that are involved in the regulation of the ageing process, and those that render age the main risk factor for many diseases are still poorly understood. Nevertheless, a growing number of compounds have been put forward to affect this process. However, for scientists and laypeople alike, it is difficult to separate fact from fiction, and hype from hope. In this review, we discuss the currently pursued pharmacological anti-ageing approaches. These are compared to non-pharmacological interventions, some of which confer powerful effects on health and well-being, in particular an active lifestyle and exercise. Moreover, functional parameters and biological clocks as well as other molecular marks are compared in terms of predictive power of morbidity and mortality. Then, conceptual aspects and roadblocks in the development of anti-ageing drugs are outlined. Finally, an overview on current and future strategies to mitigate age-related pathologies and the extension of life- and healthspan is provided

Warum reagiert mein Patient anders auf dieses Medikament? : Pharmakogenomik und personalisierte Medizin in der Praxis

Inter- und intraindividuelle Variabilität in der Arzneimittelwirkung ist häufig. Die Ursachen dieser Unterschiede sind vielseitig und bei jedem Patienten in verschiedener Kombination vorhanden. Hauptursachen sind genetische Diversität und wechselnde Umweltfaktoren wie Ernährung,andere Arzneimittel und "Lifestyle". Variabilität kann die Pharmakokinetik, z.B. den Arzneimittelabbau, oder die Pharmakodynamik, d.h. den Wirkungsmechanismus eines Medikamentes betreffen. Diese individuellen Unterschiede im Ansprechen auf ein Medikament sind ein wichtiger Teil des Konzeptes der "Personalisierten Medizin" mit dem Anspruch, für jeden Patienten eine massgeschneiderte Therapie anzuwenden, d.h. das für seine persönliche Problematik richtige Medikament in der richtigen Dosierung. Durchbrüche in den Technologien der Genomik haben dazu geführt, dass vor allem die genetische Variation der Arzneimittelwirkung besser untersucht werden kann. Diese Studien haben zu molekulargenetischen Tests geführt, die die Wirksamkeit oder das Risiko unerwünschter Nebenwirkungen besser voraussagen können. Am häufigsten wird die "Personalisierte Medizin" heute in der Krebstherapie oder bei HIV Infektionen angewandt, zunehmend aber auch in anderen therapeutischen Gebieten. Die heute bekannten Situationen, die auch für die Praxis von Bedeutung sein können, werden hier zusammengefasst. Patienten der Internet-Generation sind besser informiert über ihre Krankheit und über die Therapie, die sie erhalten. Zunehmend werden auch Patienten in der Praxis mit bereits vorhandenen Informationen zu ihrer Gensequenz oder gewissen Gentests erscheinen

Pharmacological targeting of age-related changes in skeletal muscle tissue

Sarcopenia, the age-related loss of skeletal muscle mass and function, increases the risk of developing chronic diseases in older individuals and is a strong predictor of disability and death. Because of the ongoing demographic transition, age-related muscle weakness is responsible for an alarming and increasing contribution to health care costs in Western countries. Exercise-based interventions are most successful in preventing the decline in skeletal muscle mass and in preserving or ameliorating functional capacities with increasing age. However, other treatment options are still scarce. In this review, we explore currently applied nutritional and pharmacological approaches to mitigate age-related muscle wasting, and discuss potential future therapeutic avenues

The Genomic Context and Corecruitment of SP1 Affect ERRα Coactivation by PGC-1α in Muscle Cells

The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) coordinates the transcriptional network response to promote an improved endurance capacity in skeletal muscle, eg, by coactivating the estrogen-related receptor-α (ERRα) in the regulation of oxidative substrate metabolism. Despite a close functional relationship, the interaction between these 2 proteins has not been studied on a genomic level. We now mapped the genome-wide binding of ERRα to DNA in a skeletal muscle cell line with elevated PGC-1α and linked the DNA recruitment to global PGC-1α target gene regulation. We found that, surprisingly, ERRα coactivation by PGC-1α is only observed in the minority of all PGC-1α recruitment sites. Nevertheless, a majority of PGC-1α target gene expression is dependent on ERRα. Intriguingly, the interaction between these 2 proteins is controlled by the genomic context of response elements, in particular the relative GC and CpG content, monomeric and dimeric repeat-binding site configuration for ERRα, and adjacent recruitment of the transcription factor specificity protein 1. These findings thus not only reveal a novel insight into the regulatory network underlying muscle cell plasticity but also strongly link the genomic context of DNA-response elements to control transcription factor-coregulator interactions

Coregulator-mediated control of skeletal muscle plasticity - A mini-review

Skeletal muscle plasticity is a complex process entailing massive transcriptional programs. These changes are mediated by the action of nuclear receptors and other transcription factors. In addition, coregulator proteins have emerged as important players in this process by linking transcription factors to the RNA polymerase II complex and inducing changes in the chromatic structure. An accumulating body of work highlights the pleiotropic functions of coregulator proteins in the control of tissue-specific and whole body metabolism. In skeletal muscle, several coregulators have been identified as potent modulators of metabolic and myofibrillar plasticity. In this mini-review, we will discuss the control, function and physiological significance of these coregulators in skeletal muscle biology