Slow Adhering Skeletal Muscle Cells Improve Function of Sick Hearts

Skeletal muscles consist of cells that have fused together to form a so-called “myotube.” Myotubes, upon closer examination, are filled with contractile proteins that help them contract. These rows of contractile proteins are organized into stripes, and for this reason, skeletal muscle is often called “striated muscle” because of its stripped appearance under the microscope. Skeletal muscles are collections of these myotubes all bound together, and attached to bones by means of tendons.

Skeletal muscles also contain a stem cell population called muscle satellite cells. Muscle satellite cells divide and form new muscle in response to increase demand on the muscles. Muscle satellite cells are responsible for the increase in muscle size when you lift heavy weights.

Because muscle satellite cells are easily isolated from patients, and they resist the hostile conditions of a heart that has had a heart attack, they were one of the first stem cells used to treat heart attack patients. Preclinical work on laboratory animals produced hopeful results. The implanted satellite cells did not become heart muscle cells (Reinecke H, Poppa V, Murry CE (2002) J Mol Cell Cardiol. 34(2):241-9). However, the hearts that had received satellite transplants after a heart attack showed functional improvements and no deterioration in comparison to the control animals (rats – CE Murray, et al., J. Clin. Invest. 98(11): 2512–2523; rabbits – Blatt A,, et al., Eur J Heart Fail. 2003 Dec;5(6):751-7). These positive results were the impetus for the first human clinical trials that used a patient’s own satellite muscle stem cells as a treatment for acute heart attacks.

Early trials were quite small but the implanted patients seemed to improve. Unfortunately, these early studies were not controlled terribly well, and the results somewhat hopeful, but not completely conclusive (Siminiak T., et al., Am Heart J. 2004;148(3):531-7). More controlled clinical trials, the MAGIC and MYSTAR trials, however, revealed a problem with satellite cells. They had a tendency to not connect with the resident heart muscle cells, and were, therefore, functionally isolated from the rest of the heart (Léobon B, et al., Proc Natl Acad Sci USA. 2003;100:7808–7811). Such isolation had a tendency to cause implanted hearts to beat irregularly, and for this reason, muscle satellite clinical trials have been tabled for the time being (Menasché P, et al., Circulation. 2008;117(9):1189-200).

However, skeletal muscles possess several distinct cell types and some of these are probably better candidates for heart treatments (Winitsky SO, et al., PLoS Biol. 2005;3:e87). To that end, Johnny Huard’s laboratory at the University of Pittsburgh has characterized a population of cells that show superior therapeutic possibilities from skeletal muscle.

Masaho Okada was the lead author of this paper, and he and his colleagues observed that most of the cells in skeletal muscle adhere very readily to the culture flasks after the muscle tissue was pulled apart. They designated these fast adhering cells as RACs or rapidly-adhering cells. A minority population of cells were slow-adhering cells or SACs.

Comparisons of SACs and RACs showed that the SACs were more resistant to cellular stresses than their RAC counterparts. SACs also more readily formed myotubes that RACs. The gene expression profiles of the two cell populations were also sufficiently different to confirm that even though these two cell populations were clearly derived from skeletal muscle, they were distinct populations.

Finally, transplantation of SACs into the heart of laboratory animals that had suffered heart attacks showed definitively, that SACs improved cardiac function better than RACs. Also, SACs decreased the quantity of scar tissue in the heart and increased the number of blood vessels that had formed since the heart attack. There was also less cell death in the SAC-implanted hearts as opposed to the RAC-implanted hearts.

From these data, it seems clear that the SAC population more effectively improves heart function than the RAC population. If such a population exists in the skeletal muscles of adult humans, then such cells might prove more effective for cardiac treatments than muscle satellite cells. The only caveat is that such cells may not exist in humans, since searches for such cells have not turned up anything useful to date (see Susanne Proksch, et al., Mol Ther. 2009; 17(4): 733–741).