AMPKα1 Regulates Macrophage Skewing at the Time of Resolution of Inflammation during Skeletal Muscle Regeneration

Abstract

Adult skeletal muscle has the unique capacity to regenerate. Muscle regeneration is always associated with inflammation and notably macrophages (MPs), which play dual role. Soon after injury, inflammatory monocyte‐derived macrophages (M1 phenotype) stimulate myogenic cell proliferation. After phagocytosis of muscle debris, MPs switch their phenotype to acquire an anti‐inflammatory profile (M2) and stimulate myogenic cell differentiation and myofibre growth. Here, we explored the role of AMPK in the resolution of inflammation during muscle repair. AMPKα1 KO muscle shows both a delay and an impairment of post‐injury regeneration. These deficiencies are also observed in LysM‐CRE;AMPKfl/fl muscle, confirming the MP specificity of AMPK requirement. In vitro, AMPKα1 KO MPs hardly acquire a M2 profile upon cytokine stimulation. Their phagocytic activity is also altered. In vivo analysis of MP subpopulations (using the AMPKα1−/−;CX3CR1GFP/+ mouse) during muscle repair shows that the number of intramuscular MPs exhibiting the M2 phenotype is reduced in the AMPKα1 KO compared to the WT mouse. Accordingly, leukocytes from AMPKα1 KO muscle do not increase their expression of markers associated with the resolution of inflammation during muscle regeneration. These results strongly support that AMPKα1 is one key regulator of MP switch at time of resolution of inflammation and is essential for a proper muscle repair.

AMP-activated Protein Kinase Stimulates Warburg-like Glycolysis and Activation of Satellite Cells during Muscle Regeneration

“…After induction of myogenesis, the expression of AMPK␣1 dropped first, followed by a slight increase (Fig. 1A), which is consistent with a previous report showing AMPK␣1 activity in muscle increases during muscle regeneration, whereas the activity of AMPK␣2 remain unchanged (24,28). Moreover, AMPK␣1 expression was consistently and significantly higher than AMPK␣2 in quiescent, activated, and differentiating satellite cells (Fig.…”

Cell death, clearance and immunity in the skeletal muscle

“…Another enzyme, the AMP-activated protein kinase (AMPK)-α1, which 'senses' the cellular energy levels, also regulates the inflammatory status of macrophages. AMPK-α1-deficient macrophages fail to undergo an alternative M2 activation upon the recognition of apoptotic cells, 81 suggesting a relationship between macrophage polarization and debris disposal. Studies on the cAMP response element-binding protein (CREB), a transcription factor involved in the upregulation of M2-associated genes, further strengthen the existence of a cause-effect relationship between recognition of apoptotic cells and acquisition of the macrophage ability to guide muscle stem cell regenerative potential.…”

Low-Frequency Electrical Stimulation Attenuates Muscle Atrophy in CKD—A Potential Treatment Strategy

“…In contrast, the M2 repair macrophages function in constructive processes, like wound healing and tissue repair, by producing anti-inflammatory mediators, such as arginase-1 and IL-10, which are used as markers for M2 macrophages. 23 Macrophages are normally absent or very low in abundance in muscle and usually of the M2 phenotype.…”