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.

Preserving skeletal muscle function is essential to maintain life quality at high age. Calorie restriction (CR) potently extends health and lifespan, but is largely unachievable in humans, making “CR mimetics” of great interest. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, is considered 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. Here we show that long-term CR and rapamycin unexpectedly display distinct gene expression profiles in geriatric mouse skeletal muscle, despite both benefiting aging muscles. Furthermore, CR improves muscle integrity in mice with nutrient-insensitive, sustained muscle mTORC1 activity and rapamycin provides additive benefits to CR in naturally aging mouse muscles. We conclude that rapamycin and CR exert distinct, compounding effects in aging skeletal muscle, thus opening the possibility of parallel interventions to counteract muscle aging.

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.Aging is associated with reduced cardiorespiratory fitness 1,2 and impaired responsiveness of skeletal muscle tissue to anabolic stimuli 3-5 . Skeletal muscle capillarization can affect both cardiorespiratory fitness and muscle anabolism. Enhanced capillarization ameliorates gas and metabolite exchange between blood and muscle tissue, resulting in improved peak oxygen uptake (  VO peak 2 ) and oxidative capacity 6,7 . Likewise, it has been proposed, that increased blood flow to muscles is required to support muscle fiber hypertrophy and satellite cell activation in older adults by facilitating the delivery of nutrients, cytokines and growth factors 8,9 . Furthermore, a recent study by Prior et al. 10 revealed that sarcopenic older adults have lower values for capillarization indices when compared to non-sarcopenic controls. Taken together, emerging evidence suggests that a decline in capillarization with increasing age might contribute to the development of sarcopenia and functional impairments in older adults.Endurance-type training (ET) is considered the method of choice for improving capillarization in skeletal muscle and inducing the associated local and systemic health-related benefits. While ET has consistently been demonstrated to stimulate angiogenesis and to substantially increase skeletal muscle capillarization and  VO peak 2 in older adults 6,7,11 , data on the potential of resistance training (RT) to effectively induce angiogenesis in aged muscle has been inconclusive. Some studies reported an increase in capillarization following 9-24 weeks of

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.

Background 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. Methods 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. Results 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. Conclusions 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.