Macrophages modulate skeletal muscle wasting and recovery in acute lung injury in mice
Jennifer T W Krall1, Lanazha Belfield1, Claire Strysick1
1Section on Pulmonary, Critical Care, Allergy, and Immunologic Disease, Department of Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA.
Abstract:
Skeletal muscle dysfunction in critical illnesses leaves survivors weak and functionally impaired. Macrophages infiltrate muscles; however, their functional role is unclear. We aim to examine muscle leukocyte composition and the effect of macrophages on muscle mass and function in the murine acute lung injury (ALI)-associated skeletal muscle wasting model. We performed flow cytometry of hindlimb muscle to identify myeloid cells pre-injury and time points up to 29 days after intratracheal lipopolysaccharide ALI. We evaluated muscle force and morphometrics after systemic and intramuscular clodronate-induced macrophage depletions between peak lung injury and recovery (day 5-6) versus vehicle control. Our results show muscle leukocytes changed over ALI course with day 3 neutrophil infiltration (130.5 ± 95.6cells/mg control to 236.3 ± 70.6cells/mg day 3) and increased day 10 monocyte abundance (5.0 ± 3.4%CD45+CD11b+ day 3 to 14.0 ± 2.6%CD45+CD11b+ day 10, p = 0.005). Although macrophage count did not significantly change, pro-inflammatory (27.0 ± 7.2% day 3 to 7.2 ± 3.8% day 10, p = 0.02) and anti-inflammatory (30.5 ± 11.1% day 3 to 52.7 ± 9.7% day 10, p = 0.09) surface marker expression changed over the course of ALI. Macrophage depletion following peak lung injury increased muscle mass and force generation. These data suggest muscle macrophages beyond peak lung injury limit or delay muscle recovery. Targeting macrophages could augment muscle recovery following lung injury.
Insights
Critical illness survivors experience muscle weakness. Targeting muscle macrophages after acute lung injury (ALI) improved muscle mass and function, suggesting macrophages hinder recovery.
Area of Science:
- Immunology
- Cell Biology
- Physiology
Background:
- Critical illnesses like acute lung injury (ALI) cause skeletal muscle dysfunction, leading to impaired recovery and weakness in survivors.
- Macrophages infiltrate skeletal muscle during critical illness, but their precise role in muscle wasting and recovery remains unclear.
Purpose of the Study:
- To investigate the dynamic changes in muscle leukocyte composition during ALI.
- To determine the functional impact of macrophages on skeletal muscle mass and function in a murine ALI model.
- To assess the potential of macrophage depletion as a therapeutic strategy for muscle recovery post-ALI.
Main Methods:
- Utilized flow cytometry to analyze hindlimb muscle leukocyte populations at various time points after inducing ALI via intratracheal lipopolysaccharide administration.
- Quantified skeletal muscle force generation and morphometric parameters.
- Administered clodronate to deplete macrophages systemically and intramuscularly during the recovery phase (days 5-6 post-ALI) and compared outcomes to vehicle-treated controls.
Main Results:
- Observed significant neutrophil infiltration by day 3 and increased monocyte abundance by day 10 post-ALI.
- Demonstrated dynamic shifts in macrophage surface marker expression, indicating changes in inflammatory status throughout ALI.
- Macrophage depletion post-ALI significantly enhanced muscle mass and improved muscle force generation compared to controls.
Conclusions:
- Muscle macrophages present after the peak of acute lung injury appear to impede or delay skeletal muscle recovery.
- Targeting these macrophages represents a promising therapeutic approach to augment muscle regeneration and functional recovery following critical illness.
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