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Equine March 2008 (Vol 3, No 2)

Abstract Thoughts—Pumping Iron: It's a Matter of Getting the Satellites Right

by David J. Hurley, PhD, James N. Moore, DVM, PhD

    Abstract

    Grefte S, Kuijpers-Jagtman AM, Torensma R, Von den Hoff JW. Skeletal muscle development and regeneration. Stem Cells Dev 2007;16:857-868.

    In the late stages of muscle development, a unique cell population emerges that is a key player in postnatal muscle growth and muscle regeneration. The location of these cells next to the muscle fibers triggers their designation as satellite cells. During the healing of injured muscle tissue, satellite cells are capable of forming completely new muscle fibers or restoring damaged muscle fibers. A major problem in muscle healing is the formation of dysfunctional scar tissue, which leads to incomplete functional recovery. Therefore, the identification of factors that improve the process of muscle healing and reduce the formation of scar tissue is of great interest. Because satellite cells possess the capability of self-renewal, a unique feature of stem cells, they play a central role in the search for therapies to improve muscle healing. Growth factor"based and (satellite) cell"based therapies are being investigated to treat minor muscle injuries and intrinsic muscle defects. Major muscle injury that involves the loss of muscle tissue requires the use of scaffolds with or without (satellite) cells. Scaffolds are also being developed to generate muscle tissue in vitro. These approaches aim to restore the structure and function of the injured muscle without dysfunctional scarring.

    This abstract has been reprinted with permission. The publisher for this copyrighted material is Mary Ann Liebert, Inc. publishers.

    Commentary

    For most of the uses people have for horses, it is critical for horses to have well-developed, healthy muscles. Horses are not much fun to have sitting on your lap or resting at your feet in the family room. Rather, horses are much more fun (and, in some cases, more profitable) if people are riding, jumping, showing, or racing them.

    While the development of muscle and the basics of wound healing are covered during a veterinary education, it is easy to miss the details about muscle growth and repair. To complicate matters, this field has developed significantly in the past 10 years or so.

    The article we recommend this month is a short review of muscle growth and regeneration. It is a well-written article, contains some very useful diagrams, and provides a summary of the current understanding of what controls muscle growth and development. In addition, this review provides the reader with a clearer understanding of the molecular regulators of muscle growth and repair.

    As a reminder, there are three major types of skeletal muscle myofibers. The first myofibers, commonly called type 1, are slow-twitch muscles that are resistant to fatigue. The second myofibers, called type 2A, are fast twitch; these myofibers fatigue at a moderate rate. The third myofibers, called type 2B, are fast twitch and readily fatigue. While skeletal muscle is composed of a mixture of the three types of fibers, the composition is dynamic and is subject to change with age, training, and, to some extent, load bearing.

    Muscles are capable of regeneration. This is good, as the process of training is essentially deliberate "tearing" of muscle fibers and their repair. Under ideal conditions, the muscle fibers are restored to their original condition, or even added to, with fully functional myofibers able to do the work of the original muscle with the same flexibility and range. In fact, if the training goals are met, the muscle is even better than the original muscle at doing the work.

    Restoring muscle, or "adding on to" muscle, is the job of specialized stem cells called satellite cells, which reside within the muscle structure. Like other stem cells, satellite cells can divide to maintain an active pool of cells to maintain and strengthen muscle. The number and activity of satellite cells in muscle decline with age, but these cells remain responsive to "work" in the form of exercise and loading. Satellite cells are critical because they determine whether muscle fibers will be restored and expanded or whether scarring will occur, thereby reducing muscle strength, flexibility, and function.

    Muscle fibers are torn or ruptured when they are overstretched or overloaded. This leads to invasion by inflammatory cells. The first cells to enter the muscle at the site of injury are neutrophils (and we all know that horses have a lot of these). The neutrophils set up an environment that recruits monocytes, which rapidly differentiate into macrophages—the "quarterbacks" of muscle repair and development. They activate the neutrophils in the area to engulf the debris that the muscle damage caused. They also interact directly with the satellite cells and have several effects on these cells. First, they cause the satellite cells to divide. This provides both a continuing pool of satellite cells for the future and additional satellite cells as tools to "fuse" fibers that are damaged and to "add to" the mass of fibers within a muscle.

    The macrophages also produce a large number of factors and induce surrounding muscle tissue and satellite cells to do the same. These factors (e.g., transforming growth factor Ay [TGF-aY ], fibroblast growth factors, insulin-like growth factors, hepatocyte growth factor, interleukin 6) control the fate of satellite cells. The balance between these factors causes satellite cells to differentiate; the satellite cells that migrate to the basal lamina of the muscle fibers differentiate into myoblasts. These cells either fuse with myofiber bundles to repair the damage or align with the myofiber bundles to add mass to the muscle. These two processes require a combination of the insulin-like growth factors and TGF-aY to be dominant.

    If the damage is large or multiple sites in a muscle are involved, scar formation will occur. In this case, fibro­blasts adjacent to the muscle fibers lay down collagen, predominated by type I collagen. This process is mediated by strong production of interleukin 6 by the macrophages that have been recruited and supported by the muscle itself. The presence of TGF-aY helps sustain the process of scar formation. As discussed in the January/February 2008 Abstract Thoughts, one of the consequences of running horses to exhaustion is a significant increase in interleukin 6 mRNA. So, building muscle requires the attainment of a critical balance. The training must load and stretch the muscle sufficiently to induce a local inflammatory response and activate satellite cells, but not so much that it drives the activation of fibroblasts and initiation of scarring. We are trying to determine how much inflammation is too much. Therefore, it appears that building muscle is mostly a matter of getting the satellites right.

    NEXT: Clinical Snapshot — A Deep, Intramuscular Puncture Wound in a Quarter Horse Gelding

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