Interleukin (IL)‐6 is a cytokine with pleiotropic functions in different tissues and organs. Skeletal muscle produces and releases significant levels of IL‐6 after prolonged exercise and is therefore ...considered as a myokine. Muscle is also an important target of the cytokine. IL‐6 signaling has been associated with stimulation of hypertrophic muscle growth and myogenesis through regulation of the proliferative capacity of muscle stem cells. Additional beneficial effects of IL‐6 include regulation of energy metabolism, which is related to the capacity of actively contracting muscle to synthesize and release IL‐6. Paradoxically, deleterious actions for IL‐6 have also been proposed, such as promotion of atrophy and muscle wasting. We review the current evidence for these apparently contradictory effects, the mechanisms involved and discuss their possible biological implications.
IL‐6 is a cytokine with pleiotropic functions. Skeletal muscle produces and releases IL‐6 after prolonged exercise and is considered a myokine. IL‐6 signaling stimulates hypertrophic muscle growth and de novo myogenesis. However, IL‐6 also promotes atrophy and muscle wasting. We review the current evidence for these apparently contradictory effects, the mechanisms involved and discuss their possible biological implications.
Mitochondrial dysfunction and accumulation of damaged mitochondria are considered major contributors to aging. However, the molecular mechanisms responsible for these mitochondrial alterations remain ...unknown. Here, we demonstrate that mitofusin 2 (Mfn2) plays a key role in the control of muscle mitochondrial damage. We show that aging is characterized by a progressive reduction in Mfn2 in mouse skeletal muscle and that skeletal muscle Mfn2 ablation in mice generates a gene signature linked to aging. Furthermore, analysis of muscle Mfn2‐deficient mice revealed that aging‐induced Mfn2 decrease underlies the age‐related alterations in metabolic homeostasis and sarcopenia. Mfn2 deficiency reduced autophagy and impaired mitochondrial quality, which contributed to an exacerbated age‐related mitochondrial dysfunction. Interestingly, aging‐induced Mfn2 deficiency triggers a ROS‐dependent adaptive signaling pathway through induction of HIF1α transcription factor and BNIP3. This pathway compensates for the loss of mitochondrial autophagy and minimizes mitochondrial damage. Our findings reveal that Mfn2 repression in muscle during aging is a determinant for the inhibition of mitophagy and accumulation of damaged mitochondria and triggers the induction of a mitochondrial quality control pathway.
Synopsis
Reduced muscle mitochondrial fusion protein Mfn2 is a determinant for age‐induced decay of mitochondrial function and quality, contributing to age‐associated metabolic alterations and sarcopenia.
Aging is characterized by a reduction of Mfn2 protein expression in skeletal muscle.
Reduction in Mfn2 impairs mitochondrial quality control and mitochondrial function in skeletal muscle.
Mfn2‐deficient mice show unhealthy aging characterized by impaired metabolic homeostasis and sarcopenia.
Reduction in Mfn2 triggers a mitochondrial retrograde signalling pathway in order to minimize mitochondrial damage.
Reduced muscle mitochondrial fusion protein Mfn2 is a determinant for age‐induced decay of mitochondrial function and quality, contributing to age‐associated metabolic alterations and sarcopenia.
Duchenne muscular dystrophy (DMD) is one of the most devastating neuromuscular genetic diseases caused by the absence of dystrophin. The continuous episodes of muscle degeneration and regeneration in ...dystrophic muscle are accompanied by chronic inflammation and fibrosis deposition, which exacerbate disease progression. Thus, in addition of investigating strategies to cure the primary defect by gene/cell therapeutic strategies, increasing efforts are being placed on identifying the causes of the substitution of muscle by non-functional fibrotic tissue in DMD, aiming to attenuate its severity. Congenital muscular dystrophies (CMDs) are early-onset diseases in which muscle fibrosis is also present. Here we review the emerging findings on the mechanisms that underlie fibrogenesis in muscular dystrophies, and potential anti-fibrotic treatments.
A unique property of skeletal muscle is its ability to adapt its mass to changes in activity. Inactivity, as in disuse or aging, causes atrophy, the loss of muscle mass and strength, leading to ...physical incapacity and poor quality of life. Here, through a combination of transcriptomics and transgenesis, we identify sestrins, a family of stress-inducible metabolic regulators, as protective factors against muscle wasting. Sestrin expression decreases during inactivity and its genetic deficiency exacerbates muscle wasting; conversely, sestrin overexpression suffices to prevent atrophy. This protection occurs through mTORC1 inhibition, which upregulates autophagy, and AKT activation, which in turn inhibits FoxO-regulated ubiquitin-proteasome-mediated proteolysis. This study reveals sestrin as a central integrator of anabolic and degradative pathways preventing muscle wasting. Since sestrin also protected muscles against aging-induced atrophy, our findings have implications for sarcopenia.
The repair process of damaged tissue involves the coordinated activities of several cell types in response to local and systemic signals. Following acute tissue injury, infiltrating inflammatory ...cells and resident stem cells orchestrate their activities to restore tissue homeostasis. However, during chronic tissue damage, such as in muscular dystrophies, the inflammatory-cell infiltration and fibroblast activation persists, while the reparative capacity of stem cells (satellite cells) is attenuated. Abnormal dystrophic muscle repair and its end stage, fibrosis, represent the final common pathway of virtually all chronic neurodegenerative muscular diseases. As our understanding of the pathogenesis of muscle fibrosis has progressed, it has become evident that the muscle provides a useful model for the regulation of tissue repair by the local microenvironment, showing interplay among muscle-specific stem cells, inflammatory cells, fibroblasts and extracellular matrix components of the mammalian wound-healing response. This article reviews the emerging findings of the mechanisms that underlie normal versus aberrant muscle-tissue repair.
Regeneration of skeletal muscle is a highly synchronized process that requires muscle stem cells (satellite cells). We found that localized injuries, as experienced through exercise, activate a ...myofiber self-repair mechanism that is independent of satellite cells in mice and humans. Mouse muscle injury triggers a signaling cascade involving calcium, Cdc42, and phosphokinase C that attracts myonuclei to the damaged site via microtubules and dynein. These nuclear movements accelerate sarcomere repair and locally deliver messenger RNA (mRNA) for cellular reconstruction. Myofiber self-repair is a cell-autonomous protective mechanism and represents an alternative model for understanding the restoration of muscle architecture in health and disease.
Skeletal muscles adapt to increasing workload by augmenting their fiber size, through mechanisms that are poorly understood. This study identifies the cytokine interleukin-6 (IL-6) as an essential ...regulator of satellite cell (muscle stem cell)-mediated hypertrophic muscle growth. IL-6 is locally and transiently produced by growing myofibers and associated satellite cells, and genetic loss of
IL-6 blunted muscle hypertrophy in vivo.
IL-6 deficiency abrogated satellite cell proliferation and myonuclear accretion in the preexisting myofiber by impairing STAT3 activation and expression of its target gene cyclin D1. The growth defect was indeed muscle cell intrinsic, since
IL-6 loss also affected satellite cell behavior in vitro, in a STAT3-dependent manner. Myotube-produced IL-6 further stimulated cell proliferation in a paracrine fashion. These findings unveil a role for IL-6 in hypertrophic muscle growth and provide mechanistic evidence for the contribution of satellite cells to this process.
Skeletal muscle regeneration depends on the correct expansion of resident quiescent stem cells (satellite cells), a process that becomes less efficient with aging. Here, we show that mitochondrial ...dynamics are essential for the successful regenerative capacity of satellite cells. The loss of mitochondrial fission in satellite cells—due to aging or genetic impairment—deregulates the mitochondrial electron transport chain (ETC), leading to inefficient oxidative phosphorylation (OXPHOS) metabolism and mitophagy and increased oxidative stress. This state results in muscle regenerative failure, which is caused by the reduced proliferation and functional loss of satellite cells. Regenerative functions can be restored in fission-impaired or aged satellite cells by the re-establishment of mitochondrial dynamics (by activating fission or preventing fusion), OXPHOS, or mitophagy. Thus, mitochondrial shape and physical networking controls stem cell regenerative functions by regulating metabolism and proteostasis. As mitochondrial fission occurs less frequently in the satellite cells in older humans, our findings have implications for regeneration therapies in sarcopenia.
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•Mitochondrial fission increases in satellite cells (SCs) after muscle injury•Mitochondrial fission boosts SC proliferation by inducing OXPHOS and proteostasis•DRP1 loss in SCs (genetically or during aging) impairs muscle regeneration•Normalizing mitochondrial dynamics in aged SCs restores muscle regeneration
Hong et al. illustrate that mitochondrial dynamics are required for tissue regeneration. Mitochondrial fission facilitates stem cell function via OXPHOS and mitophagy regulation. The genetic (or aging-related) loss of the mitochondrial fission regulator DRP1 in muscle stem cells blunts their proliferation and regenerative capacity, whereas DRP1 re-establishment rescues these defects.
During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. ...How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.
In response to skeletal muscle injury, distinct cellular pathways are activated to repair the damaged tissue. Activation and restriction of these pathways must be temporally coordinated in a precise ...sequence as regeneration progresses if muscle integrity and homeostasis are to be restored. However, if tissue injury persists, as in severe muscular dystrophies, the repair process becomes uncontrolled leading to the substitution of myofibers by a non-functional mass of fibrotic tissue. In this review, we provide an overview of how muscle responds to damage and aging, with special emphasis on the cellular effectors and the regulatory and inflammatory pathways that can shift normal muscle repair to fibrosis development.
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