CCR2 Inhibition Promotes Muscle Regeneration in Aged Mice

Chronic inflammation is an important component of aging. The immune system becomes overactive, provoked by a range of problems that include persistent viral infections, increased amounts of molecular debris from dead and damaged cells, and the pro-inflammatory signaling of growing numbers of senescent cells. Inflammation is useful and even necessary in the short term, a part of the defense against pathogens and regeneration from injury. In youth, episodes of inflammation are resolved when no longer needed, but this progressively ceases to be the case in older individuals.

Today's open access paper reports on research into the disruption of regeneration by chronic inflammation. Researchers are attempting to decipher the regulatory mechanisms of inflammation in various tissues and cell types to try to find ways to sabotage inflammatory processes in a usefully selective way, as simply shutting down all inflammation is very likely do more harm than good. It is worth noting, as usual, that this goal ignores the root causes of the issue. It should always be more effective to identify and address what is provoking the immune system, such as the presence of senescent cells, rather than trying to prevent downstream consequences by adjusting the operation of cellular metabolism without repairing underlying causes.

Here, the focus is on the role of the receptor CCR2 in the effects of inflammation on muscle regeneration. Research into CCR2 in the context of inflammation and age-related disease is quite varied and has been going on for some years. Looking back in the archives, there is work related to Alzheimer's disease, heart regeneration, and ventricular hypertrophy in heart failure. Much of this is connected to inflammatory macrophages, which express CCR2 and thus react to signal molecules that promote activities on the part of these cells that are disruptive to tissue function. Given that evidence, inhibition of CCR2 activity appears to have potential as a basis for therapy.

Inhibition of inflammatory CCR2 signaling promotes aged muscle regeneration and strength recovery after injury

During tissue regeneration, the recruitment of inflammatory cells is a critical early response to injury. This recruitment aids in the establishment of a favorable environment for progenitor function and tissue regeneration. Chemokines play an important role in the recruitment of inflammatory cells to sites of injury; however, persistently elevated signaling contributes to chronic inflammation associated with impaired regeneration. Among the large chemokine superfamily members, Ccl2, Ccl7, and Ccl8 bind a shared receptor, Ccr2, and have key roles in the deleterious consequences of chronic chemokine activity. As such, inhibition of Ccr2 is being pursued as a clinical therapy in disease contexts.

As a G-protein coupled transmembrane receptor, ligand-mediated activation of Ccr2 mobilizes intracellular G-proteins that help activate several pathways, including Erk and p38Mapk. Abnormal activity in these intracellular mediators has been implicated in age-related stem cell and progenitor cell dysfunction. A role for Ccr2 has also been described during skeletal muscle regeneration.

The regenerative capacity of skeletal muscle relies on a population of non-hematopoietic Pax7-expressing muscle stem cells called satellite cells (SCs). In adults, SCs reside in a primarily quiescent state. In response to a degenerative insult, SCs activate, proliferate, differentiate, and the derived progenitor cells fuse to form multinucleated muscle fibers (myofibers); thus, fulfilling skeletal muscle regeneration. Analogous to other tissues and organs, the regenerative potential of skeletal muscle declines with age. Although features of this decline include loss of SC number and function, a sub-population persists with a regenerative potential that can be stimulated.

The role of Ccr2 in non-hematopoietic cells is largely understudied, especially in the context of tissue regeneration and aging. Here, we find inflammatory-related Ccr2 expression in non-hematopoietic myogenic progenitors (MPs) during regeneration. After injury, the expression of Ccr2 in MPs corresponds to the levels of its ligands, the chemokines Ccl2, Ccl7, and Ccl8. We find stimulation of Ccr2-activity inhibits MP fusion and contribution to myofibers. High levels of Ccr2 chemokines are a feature of regenerating aged muscle. Correspondingly, deletion of Ccr2 in MPs is necessary for proper fusion into regenerating aged muscle. Finally, opportune Ccr2 inhibition after injury enhances aged regeneration and functional recovery. These results demonstrate that inflammatory-induced activation of Ccr2 signaling in myogenic cells contributes to aged muscle regenerative decline.