Adult skeletal muscle in mammals is a stable tissue under normal circumstances but has remarkable ability to repair after injury. Skeletal muscle regeneration is a highly orchestrated process invol...

Satellite Cells and the Muscle Stem Cell Niche

The muscle satellite cell was first described and actually named on the basis of its anatomic location under the basement membrane surrounding each myofiber. For many years following its discovery, electron microscopy provided the only definitive method of identification. More recently, several molecular markers have been described that can be used to detect satellite cells, making them more accessible for study at the light microscope level. Satellite cells supply myonuclei to growing myofibers before becoming mitotically quiescent in muscle as it matures. They are then activated from this quiescent state to fulfill their roles in routine maintenance, hypertrophy, and repair of adult muscle. Because muscle is able to efficiently regenerate after repeated bouts of damage, systems must be in place to maintain a viable satellite cell pool, and it was proposed over 30 years ago that self-renewal was the primary mechanism. Self-renewal entails either a stochastic event or an asymmetrical cell division, where one daughter cell is committed to differentiation whereas the second continues to proliferate or becomes quiescent. This classic model of satellite cell self-renewal and the importance of satellite cells in muscle maintenance and repair have been challenged during the past few years as bone marrow-derived cells and various intramuscular populations were shown to be able to contribute myonuclei and occupy the satellite cell niche. This is a fast-moving and dynamic field, however, and in this review we discuss the evidence that we think puts this enigmatic cell firmly back at the center of adult myogenesis.

https://journals.sagepub.com/doi/pdf/10.1369/jhc.6R6995.2006

The Skeletal Muscle Satellite Cell: The Stem Cell That Came in From the Cold:

Skeletal muscle damaged by injury or by degenerative diseases such as muscular dystrophy is able to regenerate new muscle fibers. Regeneration mainly depends upon satellite cells, myogenic progenitors localized between the basal lamina and the muscle fiber membrane. However, other cell types outside the basal lamina, such as pericytes, also have myogenic potency. Here, we discuss the main properties of satellite cells and other myogenic progenitors as well as recent efforts to obtain myogenic cells from pluripotent stem cells for patient-tailored cell therapy. Clinical trials utilizing these cells to treat muscular dystrophies, heart failure, and stress urinary incontinence are also briefly outlined.

/pdf/repairing-skeletal-muscle-regenerative-potential-of-skeletal-3wighi892t.pdf

Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells

Skeletal muscle satellite cells and adult myogenesis

Somatic stem cell populations participate in the development and regeneration of their host tissues. Skeletal muscle is capable of complete regeneration due to stem cells that reside in skeletal muscle and nonmuscle stem cell populations. However, in severe myopathic diseases such as Duchenne Muscular Dystrophy, this regenerative capacity is exhausted. In the present review, studies will be examined that focus on the origin, gene expression, and coordinated regulation of stem cell populations to highlight the regenerative capacity of skeletal muscle and emphasize the challenges for this field. Intense interest has focused on cell-based therapies for chronic, debilitating myopathic diseases. Future studies that enhance our understanding of stem cell biology and repair mechanisms will provide a platform for therapeutic applications directed toward these chronic, life-threatening diseases.

/pdf/muscle-stem-cells-in-development-regeneration-and-disease-2yxs191wrs.pdf

Muscle stem cells in development, regeneration, and disease

Activation of skeletal muscle satellite cells, defined as entry to the cell cycle from a quiescent state, is essential for normal growth and for regeneration of tissue damaged by injury or disease. This review focuses on early events of activation by signaling through nitric oxide and hepatocyte growth factor, and by mechanical stimuli. The impact of various model systems used to study activation and the regulation of satellite-cell quiescence are placed in the context of activation events in other tissues, concluding with a speculative model of alternate pathways signaling satellite-cell activation.

Signaling satellite-cell activation in skeletal muscle: markers, models, stretch, and potential alternate pathways.

Satellite cells (quiescent precursors in normal adult skeletal muscle) are activated for growth and regeneration. Signaling by nitric oxide (NO) and hepatocyte growth factor (HGF) during activation has not been examined in a model that can distinguish quiescent from activated satellite cells. We tested the hypothesis that NO and HGF are required to regulate activation using the single-fiber culture model. In normal fibers, HGF and inhibition of NO synthase (NOS) each increased activation without stretching, and NOS inhibition reduced stretchactivation. Activation in unstretched mdx and NOS-I(/ ) fibers was three- to fourfold higher than normal, and was reduced by stretching. Distinctions were not due to different pax7-expressing populations on normal and mdx fibers. The population of c-met– expressing satellite cells on normal fibers was increased by stretch, demonstrating functional heterogeneity among normal satellite cells. Cycloheximide did not prevent the stretch-related increase in c-met expression, suggesting c-met may be an immediate– early gene in satellite cell activation. Results have important implications for designing new therapies that target the role of exercise in health, aging, and disease. Developmental Dynamics 236:240 –250, 2007. © 2006 Wiley-Liss, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/dvdy.21012

Nitric oxide-dependence of satellite stem cell activation and quiescence on normal skeletal muscle fibers

Single-fiber cultures can be used to model satellite cell activation in vivo. Although technical deficiencies previously prevented study of stretch-induced events, here we describe a method developed to study satellite cell gene expression by in situ hybridization (ISH) using protocol modifications for fiber adhesion and fixation. The hypothesis that mechanical stretching activates satellite cells was tested. Fiber cultures were established from normal flexor digitorum brevis muscles and plated on FlexCell dishes with a layer of Vitrogen. After 2 hr of stretch in the presence of BrdU, satellite cells on fibers attached to Vitrogen were activated above control levels. In the absence of activating treatments or mechanical stretch, ISH studies showed 0–6 c-Met+ satellite cells per fiber. Time course experiments demonstrated stable quiescence in the absence of stretch and significant peaks in activation after 30 min and 2 hr of stretch. Frequency distributions for unstretched fiber cultures showed a significantly greater number of quiescent c-Met+ satellite cells than were activated by stretching, suggesting that typical activation stimuli did not trigger cycling in the entire c-Met+ population of satellite cells. These methods have a strong potential to further dissect the nature of stretch-induced activation and gene expression among characterized populations of individual quiescent and activated satellite cells.

https://journals.sagepub.com/doi/pdf/10.1177/002215540305101104

C-Met Expression and Mechanical Activation of Satellite Cells on Cultured Muscle Fibers

Knowledge of the events underlying satellite cell activation and the counterpart maintenance of quiescence is essential for planning therapies that will promote the growth and regeneration of skele...

Ashley C. Wozniak

Papers

Signaling satellite-cell activation in skeletal muscle: markers, models, stretch, and potential alternate pathways.

Nitric oxide-dependence of satellite stem cell activation and quiescence on normal skeletal muscle fibers

C-Met Expression and Mechanical Activation of Satellite Cells on Cultured Muscle Fibers

Satellite cell activation on fibers: modeling events in vivo — an invited review

The dynamics of the nitric oxide release-transient from stretched muscle cells.