Divergent Roles of Inflammation in Skeletal Muscle Recovery From Injury

Abstract

A transient increase in local pro-inflammatory cytokine expression following skeletal muscle injury mediates the repair and regeneration of damaged myofibers through myogenesis. Regenerative capacity is diminished and muscle wasting occurs, however, when intramuscular inflammatory signaling is exceedingly high or persists chronically. An excessive and persistent inflammatory response to muscle injury may therefore impair recovery by limiting the repair of damaged tissue and triggering muscle atrophy. The concentration-dependent activation of different downstream signaling pathways by several pro-inflammatory cytokines in cell and animal models support these opposing roles of post-injury inflammation. Understanding these molecular pathways is essential in developing therapeutic strategies to attenuate excessive inflammation and accelerate functional recovery and muscle mass accretion following muscle damage. This is especially relevant given the observation that basal levels of intramuscular inflammation and the inflammatory response to muscle damage are not uniform across all populations, suggesting certain individuals may be more susceptible to an excessive inflammatory response to injury that limits recovery. This narrative review explores the opposing roles of intramuscular inflammation in muscle regeneration and muscle protein turnover. Factors contributing to an exceedingly high inflammatory response to damage and age-related impairments in regenerative capacity are also considered.

Inflamma-miR-21 Negatively Regulates Myogenesis during Ageing

“…This is consistent with previous data that demonstrate following injury an initial elevation of IL6 and TNFα in the muscle of adult and older rodents, while the levels of IL6 and TNFα decrease approximately at day 3 in regenerating muscle of adult mice but remain elevated in muscle of old mice [41]. 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 Impact of Immune Cells on the Skeletal Muscle Microenvironment During Cancer Cachexia

“…These observations demonstrate the complexity of the ECM response and local inflammation, since they drive hypertrophy with overload and healing from damage, but are also implicated in cancer-induced muscle wasting ( Forcina et al, 2019 ). To this end, local inflammatory responses are subjected to precise temporal regulation and if this response is altered muscle remodeling can be either attenuated or blocked ( Howard et al, 2020 ), and further research is warranted to determine if cancer can disrupt the temporal aspects of local inflammation needed for successful remodeling. For example, inflammatory signaling can impact several cell types located in the muscle microenvironment leading to altered myofiber protein synthesis ( Gao et al, 2017 ) and mitochondrial quality control ( Gomez-Cabrera et al, 2016 ), which are known drivers of muscle wasting with cancer.…”

“…Depending on the extent of the damage, successful muscle regeneration including the initiation and resolution of local inflammatory processes involves infiltrating monocytes, resident MΦs, neutrophils, and T-cells ( Morgan and Partridge, 2020 ). Local inflammatory responses are subjected to precise temporal regulation and if this response is altered muscle remodeling can be either attenuated or blocked ( Howard et al, 2020 ), and further research is warranted to determine if cancer can disrupt the temporal aspects of local inflammation that contribute to disrupted satellite cell regulation of differentiation in cachectic muscle.…”

“…Chronic systemic inflammation is a widely investigated driver of muscle wasting through its direct effects on skeletal muscle ( Baracos et al, 2018 ), and its ability to induce other systemic disruptions that can ultimately regulate skeletal muscle mass, such as insulin resistance and hypogonadism ( Wu and Ballantyne, 2017 ). The ability to regenerate from injury is a recognized property of healthy skeletal muscle, and immune cells have a well-established role in this regenerative process ( Howard et al, 2020 ). While inflammation’s contribution to initiating and accelerating cancer cachexia has been widely investigated ( Evans et al, 2008 ; Carson and Baltgalvis, 2010 ), a major focus of this research has centered on circulating inflammatory mediators and how they directly regulate muscle intracellular signaling to disrupt protein turnover and metabolism to drive wasting ( Talbert et al, 2018 ).…”

“…These adaptive processes are often coupled to local inflammatory responses initiated by remodeling stimuli. These inflammatory responses are subjected to precise temporal regulation and if this response is altered, muscle remodeling can be either attenuated or blocked ( Howard et al, 2020 ). Moreover, systemic and intrinsic stimuli can induce MΦs to initiate signaling that regulates muscle fibroblasts, satellite cells, endothelial/vascular cells, as well as within the myofiber ( Tidball, 2002 ; Arnold et al, 2007 ; Fry et al, 2014 ).…”