Depending on the inflammatory milieu, injury can result either in a tissue's complete regeneration or in its degeneration and fibrosis, the latter of which could potentially lead to permanent organ failure Yet how inflammatory cells regulate matrix-producing cells involved in the reparative process is unknown Here we show that in acutely damaged skeletal muscle, sequential interactions between multipotent mesenchymal progenitors and infiltrating inflammatory cells determine the outcome of the reparative process We found that infiltrating inflammatory macrophages, through their expression of tumor necrosis factor (TNF), directly induce apoptosis of fibro/adipogenic progenitors (FAPs) In states of chronic damage, however, such as those in mdx mice, macrophages express high levels of transforming growth factor β1 (TGF-β1), which prevents the apoptosis of FAPs and induces their differentiation into matrix-producing cells Treatment with nilotinib, a kinase inhibitor with proposed anti-fibrotic activity, can block the effect of TGF-β1 and reduce muscle fibrosis in mdx mice Our findings reveal an unexpected anti-fibrotic role of TNF and suggest that disruption of the precisely timed progression from a TNF-rich to a TGF-β-rich environment favors fibrotic degeneration of the muscle during chronic injury

Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors

The world population is ageing rapidly. As society ages, the incidence of physical limitations is dramatically increasing, which reduces the quality of life and increases healthcare expenditures. In western society, ~30% of the population over 55 years is confronted with moderate or severe physical limitations. These physical limitations increase the risk of falls, institutionalization, co-morbidity, and premature death. An important cause of physical limitations is the age-related loss of skeletal muscle mass, also referred to as sarcopenia. Emerging evidence, however, clearly shows that the decline in skeletal muscle mass is not the sole contributor to the decline in physical performance. For instance, the loss of muscle strength is also a strong contributor to reduced physical performance in the elderly. In addition, there is ample data to suggest that motor coordination, excitation-contraction coupling, skeletal integrity, and other factors related to the nervous, muscular, and skeletal systems are critically important for physical performance in the elderly. To better understand the loss of skeletal muscle performance with ageing, we aim to provide a broad overview on the underlying mechanisms associated with elderly skeletal muscle performance. We start with a system level discussion and continue with a discussion on the influence of lifestyle, biological, and psychosocial factors on elderly skeletal muscle performance. Developing a broad understanding of the many factors affecting elderly skeletal muscle performance has major implications for scientists, clinicians, and health professionals who are developing therapeutic interventions aiming to enhance muscle function and/or prevent mobility and physical limitations and, as such, support healthy ageing.

/pdf/skeletal-muscle-performance-and-ageing-8ctvfggu27.pdf

Skeletal muscle performance and ageing

Adult muscle stem cells, or satellite cells have essential roles in homeostasis and regeneration of skeletal muscles. Satellite cells are located within a niche that includes myofibers and extracellular matrix. The function of specific extracellular matrix molecules in regulating SCs is poorly understood. Here, we show that the extracellular matrix protein collagen VI is a key component of the satellite cell niche. Lack of collagen VI in Col6a1(-/-) mice causes impaired muscle regeneration and reduced satellite cell self-renewal capability after injury. Collagen VI null muscles display significant decrease of stiffness, which is able to compromise the in vitro and in vivo activity of wild-type satellite cells. When collagen VI is reinstated in vivo by grafting wild-type fibroblasts, the biomechanical properties of Col6a1(-/-) muscles are ameliorated and satellite cell defects rescued. Our findings establish a critical role for an extracellular matrix molecule in satellite cell self-renewal and open new venues for therapies of collagen VI-related muscle diseases.

/pdf/collagen-vi-regulates-satellite-cell-self-renewal-and-muscle-18tw50t1hr.pdf

Collagen VI regulates satellite cell self-renewal and muscle regeneration

Tissue injury triggers a complex series of cellular responses, starting from inflammation activated by tissue and cell damage and proceeding to healing. By clearing cell debris, activating and resolving inflammation and promoting fibrosis, macrophages play key roles in most, if not all, phases of the response to injury. Recent studies of the mechanisms underlying the initial inflammation and later tissue regeneration and repair revealed that macrophages bridge these processes in part by supporting and activating stem/progenitor cells, clearing damaged tissue, remodeling extracellular matrix to prepare scaffolding for regeneration and promoting angiogenesis. However, macrophages also have a central role in the development of pathology induced by failed resolution (e.g. chronic inflammation) and excessive scarring. In this review, we summarize the activities of macrophages in inflammation and healing in response to acute injury in tissues with differing regenerative capacities. While macrophages lead similar processes in response to tissue injury in these tissues, their priorities and the consequences of their activities differ among tissues. Moreover, the magnitude, nature and duration of injury also greatly affect cellular responses and healing processes. In particular, continuous injury and/or failed resolution of inflammation leads to chronic ailments in which macrophage activities may become detrimental.

/pdf/macrophages-in-inflammation-repair-and-regeneration-5ac5vkt49v.pdf

Macrophages in inflammation, repair and regeneration.

Worldwide estimates predict 2 billion people will be aged over 65 years by 2050. A major current challenge is maintaining mobility and quality of life into old age. Impaired mobility is often a precursor of functional decline, disability and loss of independence. Sarcopenia which represents the age-related decline in muscle mass is a well-established factor associated with mobility limitations in older adults. However, there is now evidence that not only changes in muscle mass but other factors underpinning muscle quality including composition, metabolism, aerobic capacity, insulin resistance, fat infiltration, fibrosis and neural activation may also play a role in the decline in muscle function and impaired mobility associated with ageing. Importantly, changes in muscle quality may precede loss of muscle mass and therefore provide new opportunities for the assessment of muscle quality particularly in middle-aged adults who could benefit from interventions to improve muscle function. This review will discuss the accumulating evidence that in addition to muscle mass, factors underpinning muscle quality influence muscle function and mobility with age. Further development of tools to assess muscle quality in community settings is needed. Preventative diet, exercise or treatment interventions particularly in middle-aged adults at the low end of the spectrum of muscle function may help preserve mobility in later years and improve healthspan.

/pdf/it-is-not-just-muscle-mass-a-review-of-muscle-quality-3wll7gufs5.pdf

It is not just muscle mass: a review of muscle quality, composition and metabolism during ageing as determinants of muscle function and mobility in later life

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.

/pdf/aberrant-repair-and-fibrosis-development-in-skeletal-muscle-3u1tqpv1ic.pdf

Susana Aguilar

Papers

Aberrant repair and fibrosis development in skeletal muscle