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 Role of the Skeletal Muscle Secretome in Mediating Endurance and Resistance Training Adaptations

Exercise, in the form of endurance or resistance training, leads to specific molecular and cellular adaptions not only in skeletal muscles, but also in many other organs such as the brain, liver, fat or bone. In addition to direct effects of exercise on these organs, the production and release of a plethora of different signaling molecules from skeletal muscle are a centerpiece of systemic plasticity. Most studies have so far focused on the regulation and function of such myokines in acute exercise bouts. In contrast, the secretome of long-term training adaptation remains less well understood, and the contribution of non-myokine factors, including metabolites, enzymes, microRNAs or mitochondrial DNA transported in extracellular vesicles or by other means, is underappreciated. In this review, we therefore provide an overview on the current knowledge of endurance and resistance exercise-induced factors of the skeletal muscle secretome that mediate muscular and systemic adaptations to long-term training. Targeting these factors and leveraging their functions could not only have broad implications for athletic performance, but also for the prevention and therapy in diseased and elderly populations

Interleukin-6 potentiates endurance training adaptation and improves functional capacity in old mice

Interventions to preserve functional capacities at advanced age are becoming increasingly important. So far, exercise provides the only means to counteract age-related decrements in physical performance and muscle function. Unfortunately, the effectiveness of exercise interventions in elderly populations is hampered by reduced acceptance and compliance as well as disuse complications. We therefore studied whether application of interleukin-6 (IL-6), a pleiotropic myokine that is induced by skeletal muscle activity and exerts broad systemic effects in response to exercise, affects physical performance and muscle function alone or in combination with training in aged mice.; Sedentary old male mice (Sed+Saline, n = 15) were compared with animals that received recombinant IL-6 (rIL-6) in an exercise-mimicking pulsatile manner (Sed+IL-6, n = 16), were trained with a moderate-intensity, low-volume endurance exercise regimen (Ex+Saline, n = 13), or were exposed to a combination of these two interventions (Ex+IL-6, n = 16) for 12 weeks. Before and at the end of the intervention, mice underwent a battery of tests to quantify endurance performance, muscle contractility in situ, motor coordination, and gait and metabolic parameters.; Mice exposed to enhanced levels of IL-6 during endurance exercise bouts showed superior improvements in endurance performance (33% more work and 12% greater peak power compared with baseline), fatigue resistance in situ (P = 0.0014 vs. Sed+Saline; P = 0.0199 vs. Sed+IL-6; and P = 0.0342 vs. Ex+Saline), motor coordination (rotarod performance, P = 0.0428), and gait (gait speed, P = 0.0053) following training. Pulsatile rIL-6 treatment in sedentary mice had only marginal effects on glucose tolerance and some gait parameters. No increase in adverse events or mortality related to rIL-6 treatment was observed.; Administration of rIL-6 paired with treadmill running bouts potentiates the adaptive response to a moderate-intensity low-volume endurance exercise regimen in old mice, while being safe and well tolerated

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

As global life expectancy continues to climb, maintaining skeletal muscle function is increasingly essential to ensure a good life quality for aging populations. Calorie restriction (CR) is the most potent and reproducible intervention to extend health and lifespan, but is largely unachievable in humans. Therefore, identification of "CR mimetics" has received much attention. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, has been proposed as a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Contrary to our expectation, long-term CR and rapamycin-treated geriatric mice display distinct skeletal muscle gene expression profiles despite both conferring benefits to aging skeletal muscle. Furthermore, CR improved muscle integrity in a mouse with nutrient-insensitive sustained muscle mTORC1 activity and rapamycin provided additive benefits to CR in aging mouse muscles. Therefore, RM and CR exert distinct, compounding effects in aging skeletal muscle, opening the possibility of parallel interventions to counteract muscle aging

Molecular transducers of exercise training adaptations in young and aged skeletal muscle

Besides neurodegeneration, musculoskeletal weakness is the main cause for the loss of independence and nursing home placement in elderly individuals. The high morbidity, mortality and costs associated with functional degeneration and linked comorbidities are a major threat to healthcare systems and society. Exercise training, even when applied later in life, is the single most effective intervention to preserve and/or improve muscle function and cardiovascular deficits but also shows significant benefits in preventing and/or treating neurodegenerative disorders and other diseases related to a sedentary life style or aging. However, the molecular mechanisms underlying the potent effect of exercise are still poorly understood. Consequently, alternative treatment options for partially or fully exercise intolerant populations or individuals unwilling to exercise are lacking. The overarching goal of this thesis was to improve the mechanistic understanding of exercise training adaptation to foster the development of novel pharmacological and/or exercise-based therapies to preserve and/or enhance cardiovascular and muscle function. First, the potential of recombinant IL-6 to act as a therapeutic agent for the treatment and/or prevention of age-related frailty was tested in old mice. Second, a comprehensive characterization of the systemic and muscle-specific adaptations to voluntary low-load (Run) and progressive resistance (RR) wheel running in young mice was performed. Third, an innovative tool to study the mechanisms by which PGC-1α mediates endurance exercise adaptions in skeletal muscle in vivo was finalized, validated and applied. IL-6 combined with exercise bouts potentiated the adaptive response of skeletal muscle to endurance training, characterized by superior fatigue resistance. In sedentary mice, IL-6 had only minor effects on the assessed outcome measures. However, the treatment appeared to be safe and well tolerated in both trained and untrained animals. Both wheel running-based training modalities increased V̇O2peak, while Run more strongly improved submaximal running performance compared to RR. Conversely, only RR induced gains in grip strength and more effectively increased M. soleus mass, most likely via connective tissue and/or extracellular matrix remodeling. The PGC-1α1 protein-interactome was found to massively expand and change its composition in response to a single bout of exhaustive treadmill running in a time-dependent manner. In addition, a series of experiments indicated that the exact expression pattern of the alternative promoter has to be clarified, in particular regarding the independent expression of the alternative first exons E1b and E1c. Finally, besides potential shorter isoforms, our results suggested that a large amount of PGC-1α that arises from the alternative promoter following exercise is the full-length variant. The observed effects of IL-6 treatment point towards a direct role of the systemic increase of this myokine in training adaptation, at least in older mice. If these results can be translated to elderly individuals, IL-6 treatment could not only improve training interventions, and hence increase adherence and compliance, but also directly result in massive improvement of quality of life. This would be of great value to overcome one of the biggest challenges of exercise-based interventions in elderly populations – the reduced training response or even exercise intolerance. We conclude that RR provides a hybrid stimulus of endurance- and resistance-exercise components and thereby elicits the complete spectrum of structural, functional and metabolic training adaptations. RR could therefore be used as translational model for concurrent training in humans. Moreover, collective data from this study will facilitate training model selection for exercise and muscle researchers and thereby help to elucidate the mechanisms underlying exercise training adaptation. Investigation of targets emerging from the protein-interactome data set and additional future experiments enabled by the PGC-1α1 tagged mouse will advance our understanding of how this coregulator protein mediates an endurance-training phenotype

Effects of high-resistance wheel running on hallmarks of endurance and resistance training adaptations in mice

Exercise effectively promotes and preserves cardiorespiratory, neuromuscular, metabolic, and cognitive functions throughout life. The molecular mechanisms underlying the beneficial adaptations to exercise training are, however, still poorly understood. To improve the mechanistic study of specific exercise training adaptations, standardized, physiological, and well-characterized training interventions are required. Therefore, we performed a comprehensive interrogation of systemic changes and muscle-specific cellular and molecular adaptations to voluntary low-resistance wheel running (Run) and progressive high-resistance wheel running (RR) in young male mice. Following 10 weeks of training, both groups showed similar improvements in body composition and peak oxygen uptake (V̇O; 2peak; ), as well as elevated mitochondrial proteins and capillarization markers in the M. plantaris. Run mice clearly outperformed RR mice in a forced treadmill running capacity test, while RR mice displayed increased grip strength as well as superior mass gains in the M. soleus, associated with distinct proteomic changes specifying the two paradigms. Thus, even though both training modalities induce overlapping adaptations, Run interventions preferably improve submaximal running performance, while progressive RR is a valid model to study training-induced gains in grip strength and plantar flexor hypertrophy

Impaired age-associated mitochondrial translation is mitigated by exercise and PGC-1α

Sarcopenia, the age-related loss of skeletal muscle mass and function, can dramatically impinge on quality of life and mortality. While mitochondrial dysfunction and imbalanced proteostasis are recognized as hallmarks of sarcopenia, the regulatory and functional link between these processes is underappreciated and unresolved. We therefore investigated how mitochondrial proteostasis, a crucial process that coordinates the expression of nuclear- and mitochondrial-encoded mitochondrial proteins with supercomplex formation and respiratory activity, is affected in skeletal muscle aging. Intriguingly, a robust mitochondrial translation impairment was observed in sarcopenic muscle, which is regulated by the peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) with the estrogen-related receptor α (ERRα). Exercise, a potent inducer of PGC-1α activity, rectifies age-related reduction in mitochondrial translation, in conjunction with quality control pathways. These results highlight the importance of mitochondrial proteostasis in muscle aging, and elucidate regulatory interactions that underlie the powerful benefits of physical activity in this context

Resistance training preserves high-intensity interval training induced improvements in skeletal muscle capillarization of healthy old men: a randomized controlled trial

Skeletal muscle capillarization is a determining factor in gas and metabolite exchange, while its impairments may contribute to the development of sarcopenia. Studies on the potential of resistance training (RT) to induce angiogenesis in older muscles have been inconclusive, and effects of sequential endurance training (ET) and RT on capillarization are unknown. Healthy older men (66.5 ± 3.8 years) were engaged in either 12 weeks of habitual course observation (HC) followed by 12 weeks of RT (n = 8), or 12 weeks of high-intensity interval training (HIIT) followed by 12 weeks of RT (n = 9). At baseline, following 12 and 24 weeks, m. vastus lateralis biopsies were obtained. (Immuno-)histochemistry was used to assess indices of muscle fiber capillarization, muscle fiber morphology and succinate dehydrogenase (SDH) activity. Single periods of RT and HIIT resulted in similar improvements in capillarization and SDH activity. During RT following HIIT, improved capillarization and SDH activity, as well as muscle fiber morphology remained unchanged. The applied RT and HIIT protocols were thus similarly effective in enhancing capillarization and oxidative enzyme activity and RT effectively preserved HIIT-induced adaptations of these parameters. Hence, both, RT and HIIT, are valid training modalities for older men to improve skeletal muscle vascularization.ISSN:2045-232

RNA-bound PGC-1α controls gene expression in liquid-like nuclear condensates

Plasticity of cells, tissues, and organs is controlled by the coordinated transcription of biological programs. However, the mechanisms orchestrating such context-specific transcriptional networks mediated by the dynamic interplay of transcription factors and coregulators are poorly understood. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a prototypical master regulator of adaptive transcription in various cell types. We now uncovered a central function of the C-terminal domain of PGC-1α to bind RNAs and assemble multiprotein complexes including proteins that control gene transcription and RNA processing. These interactions are important for PGC-1α recruitment to chromatin in transcriptionally active liquid-like nuclear condensates. Notably, such a compartmentalization of active transcription mediated by liquid-liquid phase separation was observed in mouse and human skeletal muscle, revealing a mechanism by which PGC-1α regulates complex transcriptional networks. These findings provide a broad conceptual framework for context-dependent transcriptional control of phenotypic adaptations in metabolically active tissues