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

The molecular athlete: exercise physiology from mechanisms to medals

Human skeletal muscle demonstrates remarkable plasticity, adapting to numerous external stimuli including the habitual level of contractile loading. Accordingly, muscle function and exercise capacity encompass a broad spectrum, from inactive individuals with low levels of endurance and strength, to elite athletes who produce prodigious performances underpinned by pleiotropic training-induced muscular adaptations. Our current understanding of the signal integration, interpretation and output coordination of the cellular and molecular mechanisms that govern muscle plasticity across this continuum is incomplete. As such, training methods and their application to elite athletes largely rely on a "trial and error" approach with the experience and practices of successful coaches and athletes often providing the bases for "post hoc" scientific enquiry and research. This review provides a synopsis of the morphological and functional changes along with the molecular mechanisms underlying exercise adaptation to endurance- and resistance-based training. These traits are placed in the context of innate genetic and inter-individual differences in exercise capacity and performance, with special considerations given to the ageing athletes. Collectively, we provide a comprehensive overview of skeletal muscle plasticity in response to different modes of exercise, and how such adaptations translate from "molecules to medals"

Paracrine cross-talk between skeletal muscle and macrophages in exercise by PGC-1α-controlled BNP

Activation of resident and infiltrating immune cells is a central event in training adaptation and other contexts of skeletal muscle repair and regeneration. A precise orchestration of inflammatory events in muscle fibers and immune cells is required after recurrent contraction-relaxation cycles. However, the mechanistic aspects of this important regulation remain largely unknown. We now demonstrate that besides a dominant role in controlling cellular metabolism, the peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) also has a profound effect on cytokine expression in muscle tissue. Muscle PGC-1α expression results in activation of tissue-resident macrophages, at least in part mediated by PGC-1α-dependent B-type natriuretic peptide (BNP) production and secretion. Positive effects of exercise in metabolic diseases and other pathologies associated with chronic inflammation could accordingly involve the PGC-1α-BNP axis and thereby provide novel targets for therapeutic approaches

Muscle PGC-1α modulates satellite cell number and proliferation by remodeling the stem cell niche

BACKGROUND: The myogenic capacity of satellite cells (SCs), adult muscle stem cells, is influenced by aging, exercise, and other factors. In skeletal muscle, the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a key regulator of oxidative metabolism and endurance training adaptation. However, a link between PGC-1α and SC behavior remains unexplored. METHODS: We have now studied SC function in a PGC-1α fiber-specific gain-of-function animal model. RESULTS: In surprising contrast to bona fide exercise, muscle-specific PGC-1α transgenic mice have lower SC numbers. Nevertheless, SCs from these mice have a higher propensity for activation and proliferation. Intriguingly, muscle PGC-1α triggers a remodeling of the SC niche by altering the extracellular matrix composition, including the levels of fibronectin, which affects the proliferative output of SCs. CONCLUSIONS: Taken together, PGC-1α indirectly affects SC plasticity in skeletal muscle and thereby might contribute to improved SC activation in exercise

PGC-1alpha modulates necrosis, inflammatory response, and fibrotic tissue formation in injured skeletal muscle

BACKGROUND: Skeletal muscle tissue has an enormous regenerative capacity that is instrumental for a successful defense against muscle injury and wasting. The peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) exerts therapeutic effects in several muscle pathologies, but its role in damage-induced muscle regeneration is unclear. METHODS: Using muscle-specific gain- and loss-of-function models for PGC-1alpha in combination with the myotoxic agent cardiotoxin (CTX), we explored the role of this transcriptional coactivator in muscle damage and inflammation. RESULTS: Interestingly, we observed PGC-1alpha-dependent effects at the early stages of regeneration, in particular regarding macrophage accumulation and polarization from the pro-inflammatory M1 to the anti-inflammatory M2 type, a faster resolution of necrosis and protection against the development of fibrosis after multiple CTX-induced injuries. CONCLUSIONS: PGC-1alpha exerts beneficial effects on muscle inflammation that might contribute to the therapeutic effects of elevated muscle PGC-1alpha in different models of muscle wasting

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

Remodeling of metabolism and inflammation by exercise ameliorates tumor-associated anemia

A considerable number of patients with cancer suffer from anemia, which has detrimental effects on quality of life and survival. The mechanisms underlying tumor-associated anemia are multifactorial and poorly understood. Therefore, we aimed at systematically assessing the patho-etiology of tumor-associated anemia in mice. We demonstrate that reduced red blood cell (RBC) survival rather than altered erythropoiesis is driving the development of anemia. The tumor-induced inflammatory and metabolic remodeling affect RBC integrity and augment splenic phagocyte activity promoting erythrophagocytosis. Exercise training normalizes these tumor-associated abnormal metabolic profiles and inflammation and thereby ameliorates anemia, in part, by promoting RBC survival. Fatigue was prevented in exercising tumor-bearing mice. Thus, exercise has the unique potential to substantially modulate metabolism and inflammation and thereby counteracts pathological remodeling of these parameters by the tumor microenvironment. Translation of this finding to patients with cancer could have a major impact on quality of life and potentially survival

Molecular control of endurance training adaptation in male mouse skeletal muscle

Skeletal muscle has an enormous plastic potential to adapt to various external and internal perturbations. Although morphological changes in endurance-trained muscles are well described, the molecular underpinnings of training adaptation are poorly understood. We therefore aimed to elucidate the molecular signature of muscles of trained male mice and unravel the training status-dependent responses to an acute bout of exercise. Our results reveal that, even though at baseline an unexpectedly low number of genes define the trained muscle, training status substantially affects the transcriptional response to an acute challenge, both quantitatively and qualitatively, in part associated with epigenetic modifications. Finally, transiently activated factors such as the peroxisome proliferator-activated receptor-γ coactivator 1α are indispensable for normal training adaptation. Together, these results provide a molecular framework of the temporal and training status-dependent exercise response that underpins muscle plasticity in training