Diving Deeper into the Biochemistry of Muscle Aging

If there is one sweeping generality to be made about cellular biochemistry, it is that everything is connected to everything else. No mechanism operates in isolation, and many areas of interest to aging research that have been studied point by point over the past few decades are all different aspects of the same larger system. This is becoming much more apparent in this age of powerful computers and advanced biotechnology: specialists can get more done with their time, and thus see more of the bigger picture within which their work rests. Today's example involves muscle aging, the dynamics of muscle stem cell populations, the role of the immune system in regeneration, and the response of muscle cells to exercise and other stresses. These three are all fairly large areas of study in and of themselves, but they overlap considerably as they are parts of a system in which everything is connected to everything else.

For a variety of reasons, of which the most important is probably nothing more than ease of access, muscle is one of the most studied of tissues. Certainly work on stem cell aging in muscle is a hot topic these days, and researchers are more capable of working with muscle stem cells than with most other types. By necessity this includes a greater knowledge of surrounding mechanisms and areas of research as well. Of particular interest in the paper linked below is the role of nitric oxide: if you look back into the Fight Aging! archives you'll find it shows up in many places in the biochemistry of aging tissues. It is near everywhere.

Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide

Aging muscle undergoes a shift in the balance between myogenic potential and fibrogenic activity so that senescent muscle suffers from a reduced capacity to repair and regenerate as it becomes increasingly fibrotic. Over time, the shift can lead to substantial accumulations of connective tissue. For example, recent findings show that the concentration of collagen in the muscles of old mice is nearly twice the concentration in young mice, corresponding to a twofold increase in muscle stiffness. Much is unknown concerning the mechanisms that drive senescent muscle toward fibrosis, but recent findings concerning fibrotic processes in dystrophic muscle or in wild-type muscle that has experienced acute injury indicate that the immune system can play important roles in regulating the balance between myogenesis and fibrosis.

Our findings show that muscle aging is associated with elevations of anti-inflammatory M2a macrophages that can increase muscle fibrosis. M2a macrophages promote muscle fibrosis by arginase-mediated hydrolysis of arginine that drives the production of ornithine that is then metabolized to produce proline required for collagen production. The amplified, profibrotic inflammatory response in injured or diseased muscle can be exacerbated by the loss of neuronal nitric oxide synthase (nNOS) from muscle. Nitric oxide (NO) generated by muscle nNOS serves many regulatory roles, but in the context of muscle inflammation, it plays a role in inhibiting extravasation of leukocytes into the damaged tissue. However, muscle-derived NO can also activate satellite cells, which are a population of muscle-specific stem cells that reside in fully differentiated muscle. Satellite cell activation is required for normal muscle regeneration and growth. Thus, loss of nNOS from dystrophic muscle shifts the myogenic/fibrotic balance toward fibrosis by loss of normal NO modulation of leukocytes and satellite cells.

Skeletal muscle aging also causes large reductions in the expression of nNOS that accompany the increase in fibrosis and the reduction in regenerative capacity experienced during muscle senescence. Thus, it is feasible that the age-related decrease in muscle nNOS expression contributes to an increase in the numbers and activation of leukocytes that promote muscle fibrosis while also leading to a reduction in the numbers of satellite cells, which would reduce the regenerative capacity of aging muscle.

We test that hypothesis in the present investigation by examining the effects of expressing a muscle-specific nNOS transgene on the numbers and phenotype of leukocyte populations in the muscle, the occurrence of fibrosis, and the prevalence of satellite cells in aging muscle. We also test whether age-related increases in macrophage populations in muscle are attributable to the age of the hematopoietic stem cell population from which they are derived, or reflect the age of the muscle in which they reside by performing heterochronic bone marrow transplantations (BMT) between young and old mice and analyzing the effects of those transplantations on muscle macrophage phenotype and fibrosis in old muscle.

Collectively, our data show that M2a macrophages in muscle increase with aging in association with increased fibrosis, and we find that preventing the reduction in nNOS expression in aging muscle prevents age-related changes in muscle macrophages and fibrosis, without affecting the prevalence of satellite cells. Our findings also show that the shift of muscle macrophages to an M2a phenotype is strongly influenced by the age of the hematopoietic cells from which they are derived.

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