The University of Arizona

Muscle Stem Cells Regulate Muscle Fiber Repair and Growth

-Ronald E. Allen, Robert Rhoads, Xiaosong Liu and Mark Morales

The end product of beef production systems is muscle, and our lab has been studying the processes governing the growth and repair of muscle. Skeletal muscle has a very effective repair mechanism that can repair damaged segments of individual fibers or major damage that results in death of the entire fiber. The cells responsible for the ability of muscle to repair are specialized muscle stem cells referred to as satellite cells. Interestingly, these muscle satellite cells play a key role in muscle fiber growth, as well. When a muscle is injured, satellite cells are stimulated to divide and then fuse together end-to-end to form a new fiber or to fuse with the damaged end of a less severely damaged fiber.

During normal growth, satellite cell divide and one of the daughter cells fuses with the neighboring muscle fiber. This process adds addition genetic material to the fiber so that it can accumulate more protein. The goal of most of our work has been to understand what signals tell satellite cells to initiate the muscle fiber repair and growth processes.

Successful growth and regeneration also must include the generation and maintenance of a blood vessel network for the exchange of oxygen and nutrients and to ensure formation of mature muscle fibers. Inadequate muscle fiber formation or inadequate blood vessel regrowth (angiogenesis) results in the development of connective tissue scarring.

Communication between muscle stem cells and cells involved in blood vessel formation seems likely, especially given the number of growth factors known to be secreted by satellite cells. In an initial attempt to characterize the interactions between the muscle and angiogenic cell populations, we developed an in vitro cell culture model composed of satellite cells and microvascular fragments of blood vessels taken from fat tissue.

We found that when three dimensional microvascular fragment cultures were layered over satellite cell monolayer cultures, angiogenesis in the microvascular fragment culture was dramatically stimulated, and this stimulation was due to the production of growth promoting agents by the satellite cells. In related experiments focusing on satellite cell activation, we conducted an initial microarray analysis of gene expression in cultured satellite cells. Included among the cellular changes observed was a significant increase in the synthesis of HIF-1, a key regulator of the synthesis of many blood vessel growth- stimulating agents.

Our experiments are pointing out the importance of coordinating repair of the muscle blood supply as well as the muscle fibers. Our work is the first to demonstrate the critical communication that must occur between muscle stem cells and blood vessel cells in order to get successful muscle growth and repair. We often take muscle repair for granted, but when it does not work as designed, we find connective tissue scars in beef carcasses, muscles that don't repair and maintain strength in aging people and muscular dystrophy in young boys.

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