Exercise and Stem Cells - Part III, Muscle Stem Cells and Mesenchymal-Derived Cells

INTRODUCTION

This week we focus more heavily upon muscle stem/progenitor cells (satellite cells) and mesenchymal-derived cells. We begin our focus upon muscle stem/progenitor cells (satellite cells) because “[t]he first effect of physical exercise is obviously found on cardiac and skeletal muscles where a role in organ homeostasis is assumed by stem cells.”(1, pp. 144-5) Therefore, understanding satellite cells (SCs) is crucial for understanding the impact exercise can have upon stem/progenitor cells. We will review published data on whether or not exercise training can reverse at least some of the negative effects of aging and other pathological conditions on muscle to help us understand the impact of exercise training on muscle stem/progenitor cells.

We will be utilizing Farup and colleagues’ review manuscript as the foundation piece for this week’s blog.(2) As we saw in last week’s post, little information is available on exercise training and medicinal signaling cells (aka mesenchymal stem/stromal cells, MSCs). That said, today we will be discussing mesenchymal-derived cells, which allows us to elucidate additional information on the effects of exercise training. “Recent evidence has revealed the importance of reciprocal functional interactions between different types of mononuclear cells in coordinating the repair of injure muscles. In particular, signals released from the inflammatory infiltrate and from mesenchymal interstitial cells (also known as fibro-adipogenic progenitors (FAPs)) appear to instruct muscle stem cells (satellite cells) to break quiescence, proliferate, and differentiate” (p. 1). FAPs are mesenchymal-derived cells that are Sca1+/PDGFRα+ and reside in the interstitial space in skeletal muscle and can contribute to muscle regeneration or to fibrosis and fat deposition. Additionally, FAPs interact with satellite cells (aka, muscle stem/progenitor cells) and cells from inflammatory pathways. “Optimal regeneration entails a sequence of events that ensures temporally coordinated interactions between SCs [satellite cells], FAPs and cells of the immune system” (p. 3).

In past blogs in this series, we focused upon effects of both acute exercise and exercise training; today, we are focused only on exercise training; we will also briefly discuss differences between aerobic exercise training versus resistance exercise training. For example, “[e]ndurance exercise training results in adipose lipolysis and attenuation of fibrosis and inflammation in adipose and skeletal muscle, independent of weight loss.”(3, p. 182) Pincu and colleagues also found that aerobic exercise did not significantly alter adipose-derived stem cell (ADSC) extracellular matrix (ECM)-associated gene expression; these results were in contrast to change in diet/weight loss. This brings us back to the comments in the “Obesity and Stem Cells” mini-series that some of the negative effects of obesity on stem and progenitor cells can be reversed because of exercise training even without weight loss. Nevertheless, weight loss is important and, as we will discuss below, so too is exercise training that is not aerobic in nature.

BACKGROUND

Sarcopenia

Although this post is in the “Exercise and Stem Cells” mini-series, we can learn much through studies on how aging and disease impact muscle stem/progenitor cells. “Aging is associated with an accelerated loss of skeletal muscle mass (sarcopenia) and with a reduced regenerative capacity of the musculature, leading to a loss of strength and function” (p. 4). As we saw last week; however, exercise training benefits the elderly and the young as well as men and women consistently with regard to stem/progenitor cells.

Therefore, while sarcopenia exists, exercise training may be an effective counter to this natural accelerated muscle loss. There are changes in the stem/progenitor cell milieu (the environment) that can alter the signaling and function of stem cells. Data demonstrating that the diminished regenerative capacity in not related to the stem/progenitor cells, per se; rather, the diminished regenerative capacity seems due to environmental changes. “In a mouse model of young and old mice sharing the circulatory system (heterochronic parabiosis model) aged SCs were rejuvenated by exposure to a young systemic environment suggesting that the tissue-specific stem cells retain their proliferative potential, but that the aged systemic environment prevents full activation” (pp. 4-5). Consequently, we can now understand two key elements:

cells that can behave properly do not because of changes in the environment.
we begin to understand why exercise training consistently benefits elderly and young populations; the satellite cells functioned properly when the environment was corrected to a healthy scenario. We come back to a point mentioned several times in our various blog posts: the environment is more important than the cell. That is, there are regenerative cells in the elderly, but the environment prohibits those cells from responding normally. Once the environment is restored to healthy conditions, cellular functionality seems to be restored.

Cachexia

Cachexia is accelerated muscle loss associated with chronic diseases that complicates recovery and is an independent predictor or morbidity and mortality. “Skeletal muscle wasting is a common phenomenon in cancer patients, and cancer-related muscle loss affects up to 80% of patients with advanced cancer, leading to poorer prognosis, reduced treatment response and increased risk of complications during surgery and chemotherapy. Ultimately, cachexia accounts for >20% of all cancer-related deaths” (p. 7). In patients with cancer-related cachexia, an expansion of the myogenic precursor pool was demonstrated, as well as influence by the tumor microenvironment. Restoration of the myogenic potential of the cells by changes in the microenvironment “promoted cell differentiation and fiber fusion and reversed muscle wasting” (p. 7). It is unknown, to our knowledge, if exercise alone can counteract this. Nevertheless, restoration of a healthy microenvironment can restore cell activity and reversed the disease in those human cachexia subjects studied. We do know that exercise training leads to positive changes in cellular microenvironments, leading to the potential that exercise may help diminish and/or reverse cachexia.

Exercise to Improve Muscle Health

“Skeletal muscle is a highly plastic tissue that adapts to stimuli, by proportionally adjusting mass and strength (resistance training) or aerobic capacity (endurance training) in response to exercise…. and even non-hypertrophying endurance endurance exercise can induce proliferation of at least some SC populations” (p. 8). As can be readily observed from that statement, there are indeed differences between training modalities. In addition, there are differences between the pathological conditions described above (sarcopenia and cachexia) and physical exercise. “For instance, in most pathological conditions FAPs are activated by physical injury, which triggers extensive changes in the microenvironment, (e.g., myofiber degeneration in muscular dystrophies) or by elevated systemic concentration of inflammatory cytokines (e.g., cachexia); by contrast, during training most of these signals are absent - except for the case of strenuous exercise - and the predominant changes occurring in exercised muscles are of metabolic (redox alterations) or biomechanical (contraction/relaxation cycles) nature” (p. 8). That is both a lengthy and packed sentence that bears re-reading. This simple difference between high intensity (strenuous exercise training) and lower intensity training may be the clue as to why there are significant differences in the benefits from high intensity (highly beneficial for stem/progenitor cells) and lower intensity (no to minimal benefit for stem/progenitor cells).

Endurance Training

“Endurance training increases insulin sensitivity and glucose tolerance, for example, via increased protein expression of insulin receptor substrate-1 (IRS-1) and GLUT4 in skeletal muscle” (p. 9). After a 12 week aerobic training program, a recent study found there was hypertrophy of both type I and IIa fibers but only an increase in stem/progenitor cells in type I fibers. As a reminder, type II fibers are the fibers that are most effected by age and contraction injuries. Moreover, “non-hypertrophying endurance exercise can induce proliferation of SC populations in hybrid fibers (type I/II) without effect on the SC content of type I or II fibers” (p. 9). Therefore, while endurance training is training exercise, it is not the same as resistance training nor does it carry the same benefits.

Resistance Training

Resistance training in several human studies found “robust increases in the number of SCs has been shown… in both young and old humans” (p. 9). Stem cell proliferation impairment in the elderly and with chronic muscular disorders have been found to originate “from alterations in cues from the SC niche or the systemic environment” (p. 9). “However, long-term resistance training can reverse the SC distribution in elderly muscle toward that of young muscle” (p.9). Once again, we see that the microenvironment is crucial in determining how cells behave. Moreover, we see another advantage of long-term resistance exercise training that does not occur with either endurance training or acute exercise: (at least, partial) reversal of muscle wasting. This is a major finding that should not be overlooked.

While the adaptations that occur through resistance training do not require damage/regeneration, “the SC-FAP interplay may have a central role in resistance training adaptations. Furthermore, detraining in elderly is accompanied by an increased amount of muscle fat infiltration which can be reversed by resistance training, and reducing ectopic fat accumulation may enhance anabolic signaling” (p. 9). Not only can type II muscle fiber reversal occur, but the also the amount of fat in muscle can be reversed through resistance exercise training. It now appears that FAPs are regulated through resistance exercise-induced hypertrophy. So, while damage/regeneration is not required, it may be that hypertrophy induces M2 macrophage (anti-inflammatory macrophage) activation and they regulate FAP activity.

DISCUSSION

Exercise induces molecular changes and adaptations that have therapeutic effects and improve both regeneration and function of many organs.(1) Plus, the satellite cells are “associated with skeletal muscle remodeling after muscle damage and/or extensive hypertrophy resulting from resistance training.”(4, p. 1) As we have seen in this series, not all exercise has the same benefit. There are significant differences in the effects from acute exercise versus exercise training. In today’s blog, we also touched on differences within exercise training - endurance training versus resistance training. It is fascinating that muscle degeneration in the elderly can be reverted back toward young muscle…not only in animal models, but also in humans. Additionally, while there are differences between pathological conditions (e.g., sarcopenia and cachexia) and physical exercise, the study of these pathological conditions has helped us advance our understanding of the effects of physical exercise.

These findings should not be taken to mean that exercise training is the magical elixir of the fountain of youth. Rather, exercise training could potentially be considered as an adjuvant to cell-based therapies to help improve their efficacy in regenerative medicine. However, care must be given to how one interprets these data and then seeks to generalize the data to populations outside of the research studies (external validity). As we have seen, there are significant differences based upon intensity of the exercise, length of exercise, how and when measurements are made on the subjects in the research studies. As such, absolute conclusions as to the clinical efficacy of utilizing exercise training as an adjuvant in regenerative medicine may be premature. Nevertheless, the data are promising and hopefully discussions around the topic will encourage further studies of the various questions surrounding exercise and stem/progenitor cells. There is great hope, but we must practice caution so that we avoid hype and what Professor Timothy Caulfied refers to as “science-ploitation.”

Next week we will continue to investigate skeletal muscle, satellite cells, and investigate regenerative medicine approaches to counteract muscle loss and sarcopenia to gain further insights on how exercise training effects stem/progenitor cells as well as the environment in which those cells live. “FAPs are emerging as a ‘cellular filter’ between external perturbations (either local or systemic changes in physical, metabolic, and inflammatory cues) and the effectors of the muscle regeneration machinery - the SC” (p. 9). As can be seen in this final quotation, we are at the point of still clarifying how the components interact, so we have much to learn in this space.

REFERENCES

Ceccarelli G, Benedetti L, Arcari ML, et al. (2017). Muscle stem cell and physical activity: what point is the debate at? Open Med; 12:144-56.
Farup J, Madaro L, Puri PL, and Mikkelsen UR. (2015). Interactions between muscle stem cells, mesenchymal-derived cells and immune cells in muscle homeostasis, regeneration and disease. Cell Death Dis; 6:e1830. doi:10.1038/cddis.2015.198
Pincu Y, Huntsman JD, Zou K, et al. (2016). Diet-induced obesity regulates adipose-resident stromal cell quantity and extracellular matrix gene expression. Stem Cell Research; 17:181-190.
Damas F, Libardi CA, Ugrinowitsch C, et al. (2018). Early- and later-phases satellite cell responses and myonuclear content with resistance training in young men. PLoS ONE; 13:e0191039 https://doi.org/10.1371/journal.pone.0191039