Maresin 1 repletion improves muscle regeneration after volumetric muscle loss
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Curated by eLife
eLife assessment
This is a compelling study on pro-inflammatory and anti-inflammatory lipids in relation to skeletal muscle injury. It convincingly identifies pro-inflammatory lipids during recovery predisposing to fibrosis, and maresin 1 as an anti-inflammatory lipid reducing fibrosis, improved muscle regeneration, partially restoring contractile function, of fundamental potential clinical application.
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Abstract
The acute traumatic or surgical loss of skeletal muscle, known as volumetric muscle loss (VML), is a devastating type of injury that results in exacerbated and persistent inflammation followed by fibrosis. The mechanisms that mediate the magnitude and duration of the inflammatory response and ensuing fibrosis after VML remain understudied, and as such, the development of regenerative therapies has been limited. To address this need, we profiled how lipid mediators, which are potent regulators of the immune response after injury, varied with VML injuries that heal or result in fibrosis. We observed that non-healing VML injuries displayed increased pro-inflammatory eicosanoids and a lack of pro-resolving lipid mediators. Treatment of VML with a pro-resolving lipid mediator synthesized from docosahexaenoic acid, called Maresin 1, ameliorated fibrosis through reduction of neutrophils and macrophages and enhanced recovery of muscle strength. These results expand our knowledge of the dysregulated immune response that develops after VML and identify a novel immuno-regenerative therapeutic modality in Maresin 1.
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Author response
Reviewer #1 (Public Review):
Loss of skeletal muscle tissue from traumatic injury is debilitating. Restoring muscle mass and function remains a challenge. Using a mouse model, the authors performed punch biopsy injuries of the tibialis anterior in which the volume of muscle loss was varied to result in either successful muscle regeneration with a smaller injury or the unsuccessful outcome of fibrosis with a larger injury. For both conditions, a novel lipidomic profiling approach was used to evaluate pro-inflammatory and anti-inflammatory lipids at key time points post-injury with respect to collagen deposition, macrophage infiltration, muscle fiber regeneration, and force produced during isometric contractions. A key finding was that while all lipids increased at 3 days post-injury (dpi) and then declined through 14 …
Author response
Reviewer #1 (Public Review):
Loss of skeletal muscle tissue from traumatic injury is debilitating. Restoring muscle mass and function remains a challenge. Using a mouse model, the authors performed punch biopsy injuries of the tibialis anterior in which the volume of muscle loss was varied to result in either successful muscle regeneration with a smaller injury or the unsuccessful outcome of fibrosis with a larger injury. For both conditions, a novel lipidomic profiling approach was used to evaluate pro-inflammatory and anti-inflammatory lipids at key time points post-injury with respect to collagen deposition, macrophage infiltration, muscle fiber regeneration, and force produced during isometric contractions. A key finding was that while all lipids increased at 3 days post-injury (dpi) and then declined through 14 dpi, pro-inflammatory lipids remained elevated during recovery from greater muscle loss which led to fibrosis. Maresin 1 was identified as an anti-inflammatory lipid that, when injected into injured muscle, reduced fibrosis, improved muscle regeneration, and partially restored the strength of contraction.
Strengths: The metabolipidomic profiling demonstrated here represents a novel approach to identifying pro-inflammatory and anti-inflammatory mediators of successful vs unsuccessful skeletal muscle regeneration. These findings may translate into a new therapeutic approach for promoting successful regeneration following volumetric muscle loss.
Weaknesses: Certain aspects of the data are overinterpreted; while some measures appear to have an adequate sample size to make sound conclusions, other measures are likely to lack sufficient statistical power given their variability. Presentation of the results would be strengthened by adhering to consistent terminology and labeling of figures throughout; specific examples are identified in recommendations to the authors. Several of the images used to illustrate differences between treatments are unconvincing because differences are not readily.
We agree with the reviewer and have scaled back some of the interpretation as well as clarified the sample sizes. We have also amended the text to maintain a consistent terminology.
Reviewer #2 (Public Review):
The study is novel and valuable to the field and provides new and important insights into the role of lipid mediators in VML injuries. By expanding our understanding of the mechanisms that regulate muscle regeneration following VML injuries, the study has the potential to guide the development of novel therapeutic interventions that promote tissue repair and recovery. The data presented in the manuscript is of good quality. The findings and conclusions are supported by a variety of different analyses (e.g., gene expression, histology, flow cytometry).
Despite the strengths of the study, some limitations are identified. Specifically, the impact of maresin 1 on macrophage phenotypes (M1/M2) could have been explored in more detail using histological or protein expression analysis. Moreover, additional data are needed to substantiate the claims about increased muscle regeneration. Lastly, the study does not address myofiber innervation, myofiber-type transitions, or motor unit remodeling.
We thank the reviewer for the suggestions and have performed a more in-depth exploration of macrophage phenotypes through additional scRNA-sequencing analysis. We have also included additional data describing how Maresin 1 impacts muscle stem cells through cyclic AMP. Respectfully, profiling myofiber innervation, motor unit remodeling and myofiber-type transitions are beyond the scope of this manuscript.
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eLife assessment
This is a compelling study on pro-inflammatory and anti-inflammatory lipids in relation to skeletal muscle injury. It convincingly identifies pro-inflammatory lipids during recovery predisposing to fibrosis, and maresin 1 as an anti-inflammatory lipid reducing fibrosis, improved muscle regeneration, partially restoring contractile function, of fundamental potential clinical application.
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Reviewer #1 (Public Review):
Loss of skeletal muscle tissue from traumatic injury is debilitating. Restoring muscle mass and function remains a challenge. Using a mouse model, the authors performed punch biopsy injuries of the tibialis anterior in which the volume of muscle loss was varied to result in either successful muscle regeneration with a smaller injury or the unsuccessful outcome of fibrosis with a larger injury. For both conditions, a novel lipidomic profiling approach was used to evaluate pro-inflammatory and anti-inflammatory lipids at key time points post-injury with respect to collagen deposition, macrophage infiltration, muscle fiber regeneration, and force produced during isometric contractions. A key finding was that while all lipids increased at 3 days post-injury (dpi) and then declined through 14 dpi, …
Reviewer #1 (Public Review):
Loss of skeletal muscle tissue from traumatic injury is debilitating. Restoring muscle mass and function remains a challenge. Using a mouse model, the authors performed punch biopsy injuries of the tibialis anterior in which the volume of muscle loss was varied to result in either successful muscle regeneration with a smaller injury or the unsuccessful outcome of fibrosis with a larger injury. For both conditions, a novel lipidomic profiling approach was used to evaluate pro-inflammatory and anti-inflammatory lipids at key time points post-injury with respect to collagen deposition, macrophage infiltration, muscle fiber regeneration, and force produced during isometric contractions. A key finding was that while all lipids increased at 3 days post-injury (dpi) and then declined through 14 dpi, pro-inflammatory lipids remained elevated during recovery from greater muscle loss which led to fibrosis. Maresin 1 was identified as an anti-inflammatory lipid that, when injected into injured muscle, reduced fibrosis, improved muscle regeneration, and partially restored the strength of contraction.
Strengths: The metabolipidomic profiling demonstrated here represents a novel approach to identifying pro-inflammatory and anti-inflammatory mediators of successful vs unsuccessful skeletal muscle regeneration. These findings may translate into a new therapeutic approach for promoting successful regeneration following volumetric muscle loss.
Weaknesses: Certain aspects of the data are overinterpreted; while some measures appear to have an adequate sample size to make sound conclusions, other measures are likely to lack sufficient statistical power given their variability. Presentation of the results would be strengthened by adhering to consistent terminology and labeling of figures throughout; specific examples are identified in recommendations to the authors. Several of the images used to illustrate differences between treatments are unconvincing because differences are not readily.
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Reviewer #2 (Public Review):
The study is novel and valuable to the field and provides new and important insights into the role of lipid mediators in VML injuries. By expanding our understanding of the mechanisms that regulate muscle regeneration following VML injuries, the study has the potential to guide the development of novel therapeutic interventions that promote tissue repair and recovery. The data presented in the manuscript is of good quality. The findings and conclusions are supported by a variety of different analyses (e.g., gene expression, histology, flow cytometry).
Despite the strengths of the study, some limitations are identified. Specifically, the impact of maresin 1 on macrophage phenotypes (M1/M2) could have been explored in more detail using histological or protein expression analysis. Moreover, additional data are …
Reviewer #2 (Public Review):
The study is novel and valuable to the field and provides new and important insights into the role of lipid mediators in VML injuries. By expanding our understanding of the mechanisms that regulate muscle regeneration following VML injuries, the study has the potential to guide the development of novel therapeutic interventions that promote tissue repair and recovery. The data presented in the manuscript is of good quality. The findings and conclusions are supported by a variety of different analyses (e.g., gene expression, histology, flow cytometry).
Despite the strengths of the study, some limitations are identified. Specifically, the impact of maresin 1 on macrophage phenotypes (M1/M2) could have been explored in more detail using histological or protein expression analysis. Moreover, additional data are needed to substantiate the claims about increased muscle regeneration. Lastly, the study does not address myofiber innervation, myofiber-type transitions, or motor unit remodeling.
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