New insight into factors that drive muscle-building stem cells

A report in the January issue of Cell Metabolism, a publication of Cell Press, provides new evidence explaining how stem cells known as satellite cells contribute to building muscles up in response to exercise.

These findings could lead to treatments for reversing or improving the muscle loss that occurs in diseases such as cancer and AIDS as well as in the normal ageing process, according to the researchers.

Researchers from the Centre for Genomic Regulation (CRG) in Barcelona, Spain, showed that a transient and local rise in an inflammatory signal, the cytokine known as interleukin-6 (IL-6), is essential for the growth of muscle fibres. The findings offer the first clear mechanism for the stem cells' incorporation into muscle and the first evidence linking a cytokine to this process, said Pura Munoz-Canoves, researcher at the CRG. 'As we learn more about how muscles grow in adults, we may uncover new methods for restoring lost muscle mass in the elderly and ill,' she added.

Skeletal muscles are made up of individual myofibres, each with many nuclei containing genetic material. As muscles are made to work harder, they adapt by bulking up each of those individual fibres, the researchers explained, but the mechanisms responsible have largely remained elusive.

Mounting evidence has shown that the growth of myofibres is limited by the need to maintain an equilibrium between the number of nuclei and the fibres' overall volume. Because mature myofibres are incapable of cell division, new nuclei must be supplied by satellite cells (muscle stem cells). Once activated, satellite cells follow an ordered set of events, including proliferation, migration, and incorporation into the myofibre, leading to its growth.

Now, the researchers Antonio Serrano, Bernat Baeza, Eusebio Perdiguero and Merce Jardi (from Pura Munoz-Canoves' group at the CRG) have found that IL-6 is an essential regulator in that process. While IL-6 was virtually undetectable in the muscles of control mice, animals whose muscles were made to work harder showed an increase in IL-6 after one day. That cytokine rise was maintained for two weeks before it declined again.

Interestingly, systemically high levels of IL-6 had earlier been implicated in the muscle wasting process, Munoz-Canoves noted. 'Having excess IL-6 is bad, but its local translation is required for muscle growth.'?Dr Serrano further found that IL-6 was produced both within myofibres and in their associated satellite cells, leading to muscle growth. In contrast, the muscles of mice lacking IL-6 did not show any significant increase in size after several weeks of overloading. The researchers also showed that IL-6 exerts its effects by inducing the proliferation of satellite cells.

While Munoz-Canoves said that the findings are 'just the beginning' of a new line of investigation into how adult muscle grows, she added that they might ultimately provide a new avenue for muscle-building therapies. 'Treatments could be designed to compensate for or block the pathways leading to muscle loss,' she said. 'In muscles that have already lost mass, you might also be able to stimulate muscle growth.'

The researchers include Antonio L. Serrano, Bernat Baeza-Raja, Eusebio Perdiguero, Merce Jardi, and Pura Munoz-Canoves, of the Program on Differentiation and Cancer, Centre for Genomic Regulation (CRG) in Barcelona and Centre for Neurodegenerative Diseases (CIBERNED), Spain.