Chronic inflammation in skeletal muscle impairs satellite cells function during regeneration: can physical exercise restore the satellite cell niche?

Abstract

Chronic inflammation impairs skeletal muscle regeneration. Although many cells are involved in chronic inflammation, macrophages seem to play an important role in impaired muscle regeneration since these cells are associated with skeletal muscle stem cell (namely, satellite cells) activation and fibro-adipogenic progenitor cell (FAP) survival. Specifically, an imbalance of M1 and M2 macrophages seems to lead to impaired satellite cell activation, and these are the main cells that function during skeletal muscle regeneration, after muscle damage. Additionally, this imbalance leads to the accumulation of FAPs in skeletal muscle, with aberrant production of pro-fibrotic factors (e.g., extracellular matrix components), impairing the niche for proper satellite cell activation and differentiation. Treatments aiming to block the inflammatory pro-fibrotic response are partially effective due to their side effects. Therefore, strategies reverting chronic inflammation into a pro-regenerative pattern are required. In this review, we first describe skeletal muscle resident macrophage ontogeny and homeostasis, and explain how macrophages are replenished after muscle injury. We next discuss the potential role of chronic physical activity and exercise in restoring the M1 and M2 macrophage balance and consequently, the satellite cell niche to improve skeletal muscle regeneration after injury.

Inflamma-miR-21 Negatively Regulates Myogenesis during Ageing

“…Furthermore, in regenerating adult muscle, a switch from M1 to M2 macrophages and T cell recruitment occurs approximately at days 3-5 [52], a time point where we observed a downregulation of miR-21 expression in regenerating muscle from adult mice only (Figure 1f). This switch from pro-to anti-inflammatory is not as effective in regenerating muscle of old mice, hence it is possible that miR-21 is upregulated in regenerating muscle from old mice (Figure 1g) due to a chronic pro-inflammatory environment [7].…”

“…The increased expression of miR-21 in muscle from old muscle, both quiescent and following injury, may be due to age-related increase in pro-inflammatory cytokines, such as TNFα or IL6, within the muscle itself or within its local or systemic niche, or exposure to H 2 O 2 . The levels of cytokines and ROS are transiently upregulated following muscle injury and have been proposed to be chronically dysregulated during ageing and contribute to defective muscle regeneration [3,7,40,41]. Primary mouse myoblasts from adult and old mice were treated with H 2 O 2 , IL6 or TNFα for 72 h, respectively, and miR-21 expression was evaluated by qPCR.…”

“…Several common mechanisms have been proposed to be associated with a loss of muscle mass and function during both ageing and cachexia, such as increased levels of proinflammatory cytokines and chronically elevated levels of reactive oxygen species (ROS) [2]. Chronic redox stress and inflammation have been proposed to contribute to muscle atrophy through regulating satellite cell function, and therefore muscle regeneration during ageing and cachexia [3][4][5][6][7]. Regeneration of adult skeletal muscle is largely dependent on satellite cell viability and functionality [8].…”

Recapitulating human tissue damage, repair, and fibrosis with human pluripotent stem cell-derived organoids

“…Additionally, the process of tissue repair in vivo is influenced by a myriad of systemic signals that can alter the intrinsic regenerative mechanisms of the organ. For example, tissue regeneration is significantly impaired in patients with chronic systemic inflammatory conditions …”

“…For example, tissue regeneration is significantly impaired in patients with chronic systemic inflammatory conditions. 1,2 On the other hand, in vitro models based on the use of human cell cultures consisting of one or multiple different cell types (co-cultures) are valuable for the study of molecular pathways but do not replicate the tissue microenvironment in vivo and therefore are not informative of cell behavior and complex cross-talk mechanisms that take place in the damaged tissue.…”