As we saw in last week’s blog post, studying pathologies such as sarcopenia and cachexia allowed us to further understand muscle stem/progenitor cells (satellite cells) and the impact exercise has on them. Today, we will use a review on regenerative medicine approaches to age-related muscle loss and sarcopenia by Naranjo and colleagues (2017) to serve as the basis for the discussion.(1) As we saw last week, exercise (particularly resistance training) can be of great benefit to those with sarcopenia, or those that may be at risk for developing sarcopenia.
Skeletal muscle has an inherent capacity to repair and regenerate following injury, which is why resistance training may be the most interesting exercise training for sarcopenia. Briefly, injury activates resident satellite cells along with regulation by innate immune response, particularly macrophages. The M1 phenotype macrophage is inflammatory as is active in the immediate response following injury as well as leading to proliferation of satellite cells and the M2 phenotype macrophages are pro-remodeling and anti-inflammatory to lead to mobilization and differentiation of satellite cells, boosting angiogenesis (development of vasculature), new extracellular matrix, and leading to the restoration of homeostasis.
Sarcopenia is “a complex and multifactorial disease that includes decrease in the number, structure and physiology of muscle fibers, and age-related muscle mass loss, and is associated with loss of strength, increased frailty, and increased risk for fractures and falls” (p. 580). Moreover, roughly 30% of older adults will be affected by sarcopenia and sarcopenia is a “major risk factor for adverse events associated with frailty, weakness, falls, immobility, functional decline, and institutionalization” (p. 581). Currently, treatment strategies fall into two broad categories: preventative measures and mitigating disease progress. Table 1 summarizes various current treatment strategies. What is readily observable from the table is that the current treatment options are suboptimal. The regenerative medicine approaches to sarcopenia discussed by Naranjo et al include “strategies to restore adequate skeletal muscle structure and function including exogenous delivery of cells and pharmacological therapies to induce myogenesis or reverse the physiologic changes that result in the disease. Approaches that modify the microenvironment to provide an environment conducive to reversal and mitigation of the disease represent a potential regenerative medicine approach” (p. 580).
Last week, we reviewed data from Farup et al (2015) demonstrating that exercise can be of great benefit to both sarcopenia and cachexia.(2) While exercise is important, “[n]utrition and exercise are the two fundamental tenants [sic] of treatment, but there is controversy regarding the relative clinical benefit of either approach” (p. 581). Farup and colleagues demonstrated that resistance training is of critical importance. As such, general physical activity rather than specific resistance training may account for the controversy and the disparate results. Various protocols have been examined and the disparate data may demonstrate that some protocols are more effective than others.
The microenvironment is crucial to successful satellite cell activation as well as repair and regeneration of muscle. “Disturbances in the responding stem/progenitor cells populations as well as the innate immune system and the microenvironment have been shown to contribute to sarcopenia. Beyond aging, muscle wasting is also associated with chronic inflammatory disease, including chronic obstructive pulmonary disease, muscular dystrophy, idiopathic myopathies, and rheumatoid arthritis, among others” (p. 581). In fact, various proinflammatory cytokines have been demonstrated to contribute to muscle loss. A constant environment of inflammation inhibits muscle repair and regeneration and leads to atrophy of the muscle.
Regenerative Medicine Approaches to Sarcopenia
1. Cellular Therapies
Delivering exogenous stem/progenitor cells to repopulate the satellite cell (muscle stem/progenitor cells) pool as a means of stimulating myogenesis has had little success. Various cell types have been investigated, including satellite cells, muscle-derived stem cells, perivascular stem cells, embryonic stem cells, and induced pluripotent stem cells. Each of these cell types have their own challenges, but they can be summarized into difficulty with delivery, cell concentration, expansion, engraftment, and associated risks (e.g, tumor generation). It is important to note that not all difficulties apply to each of the cell types investigated.
2. Biologic Scaffolds
Biologic scaffolds have also been investigated. “[I]t is becoming better understood that, in fact, the microenvironmental niche plays a significant role in contributing to the proliferative capacity of satellite cells and regeneration of skeletal muscle as a whole. When skeletal muscle regenerative capacity is impeded, it is likely due, at least in part, to the loss of inherent signals that contribute to skeletal muscle regeneration in healthy tissue” (p. 585). As Naranjo and colleagues stated, the evidence for changing the environment of aged progenitor cells to promote muscle regeneration is overwhelming. Without environmental changes, the cells do not function properly for muscle regeneration. Biologic scaffolds reproduce the natural environment and clinical data demonstrate that a healthy extracellular matrix (ECM) in a biologic scaffold “promotes myogenesis in patients with volumetric muscle loss” (p. 585). Moreover, these ECM bioscaffolds have consistently also been associated with a favourable macrophage activation in animal models. In addition to the ECM bioscaffolds themselves, contained within them are matrix-bound nanovesicles that are one of the main signaling mechanisms for biologic effects within tissues. As such, minimally invasive deliver of ECM bioscaffolds hold promise.
Traditional focus for pharmalogics have been on “anti-inflammatory drugs, steroids, hormones, and growth factors…” (p. 586). While they may help with reverting the functional decline or improving outcomes, “the do not specifically target myogenesis or directly affect the restoration of tissue function” (p. 586). Finally, the delivery methods for these are also a significant obstacle that must be overcome. If they are delivered systemically, rather than locally, their efficacy is reduced; systemic delivery reduces concentration at the particular site of need due to a suboptimal dose to avoid toxicity or other side effects. As the authors point out, if an injection of those pharmaceuticals is performed, the short-half life renders most of the drugs ineffective.
4. Resistance Training and Exercise
The primary treatment option for sarcopenia to date is exercise with load-bearing activities (e.g., resistance training). Resistance training is used because it is a strong anabolic stimulus, but the response may be impaired in these individuals. Nevertheless, ‘[m]ounting evidence has shown the importance of incorporation of mechanical loading to promote not only myogenesis, but also macrophage activation. Cezar et al corroborated the broad clinical utility of mechanical loading in the field of regenerative medicine by showing the ability of mechanical stimulation along, in a biologic-free muscle-regenerating system, to promote myogenesis in a rodent model of ischemic muscle injury.” (p. 586-7).
These findings discussed in this blog confirm the importance of exercise training, particularly resistance training, for muscle regeneration. In those with various pathologies, resistance training alone may not be the ultimate solution. However, “...the combination of focused mechanical loading with stem-cell-, pharmaceutical-, or biomaterial-based therapies could potentially enhance regenerative outcomes” (p. 587). The fact that sarcopenia is a multi-factorial disease with a complicated etiology suggests that treatment approaches may also need to involve a multidisciplinary approach. Progress in understanding the various cytokines, small molecules, cellular activity, and the microenvironment have allowed for additional progress in understanding the cause of sarcopenia and it’s progression. Moreover, the importance of the microenvironment continues to come to light. Focus on the microenvironment allows impact on numerous cell types involved in regenerating muscle. The body naturally utilizes various cells and signals in the repair and regeneration pathways, so it seems advisable to mimic this approach as part of the system of therapy. As such, focus should continue to be placed upon the milieu within the microenvironment, so that it is marked as a microenvironment of repair, regeneration, and remodeling rather than tissue destruction.
As always, medical ethics come into play when moving from research to clinical practice. While there are data to demonstrate the benefit of exercise training, and other tools used in regenerative medicine, on stem cells, making claims that are not supported by the literature are in violation of the AARM Code of Ethics in Regenerative Medicine.(3) Specifically, the “Code” states that a “physician’s treatment claims must be based on peer reviewed scientific evidence” (p. 3). For elderly patients being treated by regenerative medicine specialists, it may be important to contemplate incorporating exercise training, particularly resistance training, as this blog post and previous posts have discussed, for its potential benefit to regenerative capacity via inducing changes in the microenvironment. Nevertheless, until clinical studies are performed in this area of regenerative medicine, we are unable to conclude one way or the other.
1. Naranjo JD, Dziki JL, and Badylak SF. (2017). Regenerative medicine approaches for age-related muscle loss and sarcopenia: A mini-review. Gerontology; 63:580-9.
2. 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 and Disease; 6,e1830; doi:10.1038/cddis.2015.198.
3. Harrell DB, Qu W, Binzak-Blumenfeld B, et al. (2017). AARM Code of Ethics in Regenerative Medicine. http://www.aabrm.org/AARM-Code-of-Ethics-in-Regenerative-Medicine.pdf