Preconditioning improves muscle regeneration after ischemia–reperfusion injury

Zhong, Huanhuan; Liu, Mengyao; Kim, Hubert T.; Liu, Xuhui

doi:10.1002/jor.24909

Cited by 5 publications

(6 citation statements)

References 48 publications

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“…Preconditioning muscle before ischemic injury has been shown to improve muscle quality and function in mice as well as increase uncoupling protein 1–positive beige adipose FAP differentiation. 35…”

Section: Discussionmentioning

confidence: 99%

Defining Endogenous Mitochondrial Transfer in Muscle After Rotator Cuff Injury

Chi,

Davies,

Garcia

et al. 2024

Am J Sports Med

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Background: Rotator cuff muscle degeneration leads to poor clinical outcomes for patients with rotator cuff tears. Fibroadipogenic progenitors (FAPs) are resident muscle stem cells with the ability to differentiate into fibroblasts as well as white and beige adipose tissue. Induction of the beige adipose phenotype in FAPs has been shown to improve muscle quality after rotator cuff tears, but the mechanisms of how FAPs exert their beneficial effects have not been fully elucidated. Purpose: To study the horizontal transfer of mitochondria from FAPs to myogenic cells and examine the effects of β-agonism on this novel process. Study Design: Controlled laboratory study. Methods: In mice that had undergone a massive rotator cuff tear, single-cell RNA sequencing was performed on isolated FAPs for genes associated with mitochondrial biogenesis and transfer. Murine FAPs were isolated by fluorescence-activated cell sorting and treated with a β-agonist versus control. FAPs were stained with mitochondrial dyes and cocultured with recipient C2C12 myoblasts, and the rate of transfer was measured after 24 hours by flow cytometry. PdgfraCreERT/MitoTag mice were generated to study the effects of a rotator cuff injury on mitochondrial transfer. PdgfraCreERT/tdTomato mice were likewise generated to perform lineage tracing of PDGFRA+ cells in this injury model. Both populations of transgenic mice underwent tendon transection and denervation surgery, and MitoTag-labeled mitochondria from Pdgfra+ FAPs were visualized by fluorescent microscopy, spinning disk confocal microscopy, and 2-photon microscopy; overall mitochondrial quantity was compared between mice treated with β-agonists and dimethyl sulfoxide. Results: Single-cell RNA sequencing in mice that underwent rotator cuff tear demonstrated an association between transcriptional markers of adipogenic differentiation and genes associated with mitochondrial biogenesis. In vitro cocultures of murine FAPs with C2C12 cells revealed that treatment of cells with a β-agonist increased mitochondrial transfer compared to control conditions (17.8% ± 9.9% to 99.6% ± 0.13% P < .0001). Rotator cuff injury in PdgfraCreERT/MitoTag mice resulted in a robust increase in MitoTag signal in adjacent myofibers compared with uninjured mice. No accumulation of tdTomato signal from PDGFRA+ cells was seen in injured fibers at 6 weeks after injury, suggesting that FAPs do not fuse with injured muscle fibers but rather contribute their mitochondria. Conclusion: The authors have described a novel process of endogenous mitochondrial transfer that can occur within the injured rotator cuff between FAPs and myogenic cells. This process may be leveraged therapeutically with β-agonist treatment and represents an exciting target for improving translational therapies available for rotator cuff muscle degeneration. Clinical Relevance: Promoting endogenous mitochondrial transfer may represent a novel translational strategy to address muscle degeneration after rotator cuff tears.

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Section: Discussionmentioning

confidence: 99%

Defining Endogenous Mitochondrial Transfer in Muscle After Rotator Cuff Injury

Chi,

Davies,

Garcia

et al. 2024

Am J Sports Med

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“…We have additionally demonstrated that FAPs likely have an important role in this degenerative process given their increase in adipogenic and fibrotic gene expression noted at 6 weeks, coinciding with worsening fibrofatty degeneration of muscle by 15 weeks. The implication of FAPs in the pathogenesis of lumbar multifidus degeneration is significant, because FAPs represent a large endogenous stem cell population within muscle that can be harnessed under the proper treatment conditions to improve muscle quality after injury [ [13] , [14] , 17 , 26 ].…”

Section: Discussionmentioning

confidence: 99%

“…At 6 weeks (n = 4/group), 8 weeks (n = 4/group), 10 weeks (n = 4/group), and 12 weeks (n = 4/group) postoperatively, mice underwent DigiGait analysis (Mouse Specifics, Framingham, MA) to quantify changes in the gait patterns of the right and left hindlimbs as previously described [16] , [17] .…”

Section: Methodsmentioning

confidence: 99%

Paraspinal muscle degeneration and regenerative potential in a Murine model of Lumbar Disc Injury

Davies¹,

Kaur²,

Liu

et al. 2021

North American Spine Society Journal (NASSJ)

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Background Context: The association between low back pain and lumbar disc degeneration is not fully characterized. One potentially overlooked factor of this process is the lumbar multifidus, which plays a role in segmental stabilization and locomotion. Previous reports have shown multifidus degeneration to be associated with disc degeneration. The goal of this study was to develop a mouse model of advanced lumbar disc degeneration to recapitulate the pathology of the human multifidus in patients with lumbar disc degeneration and low back pain.Methods: C57BL/6 mice underwent a left anterolateral approach to the lumbar spine and disc puncture with a micro scalpel at L5/6 and L6/S1. Mice underwent behavioral analysis and functional gait testing. A subset of mice underwent 14T T2-weighted MRI to assess disc degeneration and paraspinal muscle quality. At 6 and 15 weeks, mice were sacrificed, and the multifidus muscles were harvested and divided into proximal and distal segments relative to disc injury. Histological analysis was performed to assess muscle degeneration, fiber type, and macrophage density. Fibroadipogenic progenitors (FAPs) were isolated for gene expression analysis with qPCR.Results: MRI demonstrated decreased intervertebral disc signal and paraspinal muscle atrophy at 6 weeks, with progressive degeneration and atrophy at 15 weeks. Disc injury resulted in delayed functional recovery and impaired gait. Histology demonstrated progressive multifidus fibrofatty degeneration between 6 and 15 weeks. CD68 + macrophage density was increased at 6 weeks but not 15 weeks. FAPs exhibited increased fibrotic and adipogenic gene expression at 6 weeks compared to sham with less of a difference in gene expression by 15 weeks. Conclusions:We have developed a mouse model of disc injury-mediated paraspinal muscle degeneration that recapitulates features of degenerative muscle pathology observed in patients with lumbar disc degeneration, and highlights the role of FAPs in mediating fibrofatty muscle degeneration after disc injury.

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“…The mice were randomly divided into Control group and MAP group ( n = 6 in each group). Mice in both groups underwent unilateral hindlimb ischemia with a rubber band on the base of right thigh for 3 h as previously described 11 . The other hindlimb was used as Contralateral side.…”

Section: Methodsmentioning

confidence: 99%

“…Mice in both groups underwent unilateral hindlimb ischemia with a rubber band on the base of right thigh for 3 h as previously described. 11 The other hindlimb was used as Contralateral side. The application of MAP treatment was performed on the same hindlimb at 1 week after the initial injury by using a compact electromagnetic unit with an unfocused acoustic pulse source (LiteMed Inc.).…”

Section: Animals and Proceduresmentioning

confidence: 99%

Microenergy acoustic pulses promotes muscle regeneration through in situ activation of muscle stem cells

Zhang

Kim

Lin

et al. 2021

Journal Orthopaedic Research

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Microenergy acoustic pulses (MAP) is a modified low‐intensity extracorporeal shock wave therapy that currently used for treating musculoskeletal disorders. However, its function on muscle regeneration after ischemia‐reperfusion injury (IRI) remains unknown. This study aimed to explore the effect of MAP on muscle injury after IRI and its underlying mechanisms. Ten‐week‐old C57BL/6J mice underwent unilateral hindlimb IRI followed with or without MAP treatment. Wet weight of tibialis anterior muscles at both injury and contralateral sides were measured followed with histology analysis at 3 weeks after IRI. In in vitro study, the myoblasts, endothelial cells and fibro‐adipogenic progenitors (FAP) were treated with MAP. Cell proliferation and differentiation were assessed, and related gene expressions were measured by real‐time PCR. Our results showed that MAP significantly increased the muscle weight and centrally nucleated regenerating muscle fiber size along with a trend in activating satellite cells. In vitro data indicated that MAP promoted myoblast proliferation and differentiation and endothelial cells migration. MAP also induced FAP brown/beige adipogenesis, a promyogenic phenotype of FAPs. Our findings demonstrate the beneficial function of MAP in promoting muscle regeneration after IR injury by inducing muscle stem cells proliferation and differentiation.

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Preconditioning improves muscle regeneration after ischemia–reperfusion injury

Cited by 5 publications

References 48 publications

Defining Endogenous Mitochondrial Transfer in Muscle After Rotator Cuff Injury

Defining Endogenous Mitochondrial Transfer in Muscle After Rotator Cuff Injury

Paraspinal muscle degeneration and regenerative potential in a Murine model of Lumbar Disc Injury

Microenergy acoustic pulses promotes muscle regeneration through in situ activation of muscle stem cells

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