scholarly journals PGC-1α overexpression partially rescues impaired oxidative and contractile pathophysiology following volumetric muscle loss injury

2019 ◽  
Author(s):  
William M. Southern ◽  
Anna S. Nichenko ◽  
Kayvan F. Tehrani ◽  
Melissa J. McGranahan ◽  
Laxminarayanan Krishnan ◽  
...  
Keyword(s):  
Oxidative Capacity ◽  
Limiting Factor ◽  
Muscle Loss ◽  
Functional Impairments ◽  
Skeletal Muscle Dysfunction ◽  
Capacity Loss ◽  
Volumetric Muscle Loss ◽  
Ablative Surgery ◽  
And Function ◽  
Injured Patients

AbstractVolumetric muscle loss (VML) injury is characterized by a non-recoverable loss of muscle fibers due to ablative surgery or severe orthopaedic trauma, that results in chronic functional impairments of the soft tissue. Currently, the effects of VML on the oxidative capacity and adaptability of the remaining injured muscle are unclear. A better understanding of this pathophysiology could significantly shape how VML-injured patients and clinicians approach regenerative medicine and rehabilitation following injury. Herein, the data indicated that VML-injured muscle has diminished mitochondrial content and function (i.e. oxidative capacity), loss of mitochondrial network organization, and attenuated oxidative adaptations to exercise. However, forced PGC-1α over-expression rescued the deficits in oxidative capacity and muscle strength. This implicates physiological activation of PGC1-α as a limiting factor in VML-injured muscle adaptive capacity and provides a mechanistic target for regenerative rehabilitation approaches to address the skeletal muscle dysfunction.

scholarly journals Early rehabilitation for volumetric muscle loss injury augments endogenous regenerative aspects of muscle strength and oxidative capacity

2018 ◽  
Vol 19 (1) ◽  
Author(s):  
Sarah M. Greising ◽  
Gordon L. Warren ◽  
W. Michael Southern ◽  
Anna S. Nichenko ◽  
Anita E. Qualls ◽  
...  
Keyword(s):  
Muscle Strength ◽  
Oxidative Capacity ◽  
Early Rehabilitation ◽  
Muscle Loss ◽  
Volumetric Muscle Loss

scholarly journals Forced PGC1a1 Expression Improves Oxidative Capacity And Partially Rescues Strength Following Volumetric Muscle Loss Injury

2018 ◽  
Vol 50 (5S) ◽  
pp. 845-846
Author(s):  
William M. Southern ◽  
Anna S. Nichenko ◽  
Anita E. Qualls ◽  
Amelia Yin ◽  
Hang Yin ◽  
...  
Keyword(s):  
Oxidative Capacity ◽  
Muscle Loss ◽  
Volumetric Muscle Loss

Secondary Denervation is a Chronic Pathophysiologic Sequela of Volumetric Muscle Loss

2021 ◽  
Author(s):  
Jacob R. Sorensen ◽  
Daniel B. Hoffman ◽  
Benjamin T. Corona ◽  
Sarah M. Greising
Keyword(s):  
Muscle Function ◽  
Neuromuscular Junctions ◽  
Muscle Loss ◽  
Functional Impairments ◽  
Traumatic Loss ◽  
Treatment Target ◽  
Volumetric Muscle Loss ◽  
Terminal Axon ◽  
Defect Area

Volumetric muscle loss (VML) is the traumatic loss of muscle tissue that results in long-term functional impairments. Despite the loss of myofibers, there remains an unexplained significant decline in muscle function. VML injury likely extends beyond the defect area, causing negative secondary outcomes to the neuromuscular system, including the neuromuscular junctions (NMJs), yet the extent to which VML induces denervation is unclear. This study systematically examined NMJs surrounding the VML injury, hypothesizing that the sequela of VML includes denervation. The VML injury removed ∼20% of the tibialis anterior (TA) muscle in adult male inbred Lewis rats (n=43), the non-injured leg served as an intra-animal control. Muscles were harvested up to 48 days post-VML. Synaptic terminals were identified immunohistochemically and quantitative confocal microscopy evaluated 2,613 individual NMJ. Significant denervation was apparent by 21 and 48 days post-VML. Initially, denervation increased ∼10% within 3 days of injury; with time, denervation further increased to ~22 and 32% by 21 and 48 days post-VML. Respectively, suggesting significant secondary denervation. The appearance of terminal axon sprouting and poly-innervation were observed as early as 7 days post-VML, increasing in number and complexity throughout 48 days. There was no evidence of VML-induced NMJ size alteration, which may be beneficial for interventions aimed at restoring muscle function. This work recognizes VML-induced secondary denervation and poor remodeling of the NMJ as part of the sequela of VML injury; moreover secondary denervation is a possible contributing factor to the chronic functional impairments and potentially an overlooked treatment target.

scholarly journals Biomimetic sponges improve muscle structure and function following volumetric muscle loss

2020 ◽  
Author(s):  
Gabriel Haas ◽  
Andrew Dunn ◽  
Josh Madsen ◽  
Peter Genovese ◽  
Andrew Lin ◽  
...  
Keyword(s):  
Significant Loss ◽  
Structure And Function ◽  
Muscle Loss ◽  
Cross Sectional ◽  
Fk 506 ◽  
Traumatic Injuries ◽  
Muscle Structure ◽  
Volumetric Muscle Loss ◽  
Isometric Torque ◽  
And Function

AbstractSkeletal muscle is inept in regenerating after traumatic injuries such as volumetric muscle loss (VML) due to significant loss of basal lamina and the resident satellite cells. Currently, there are no approved therapies for the treatment of muscle tissue following trauma. In this study, biomimetic sponges composed of gelatin, collagen, laminin-111, and FK-506 were used for the treatment of VML in a rodent model. We observed that biomimetic sponge treatment improved muscle structure and function while modulating inflammation and limiting the extent of fibrotic tissue deposition. Specifically, sponge treatment increased the total number of myofibers, type 2B fiber cross-sectional area, myosin: collagen ratio, myofibers with central nuclei, and peak isometric torque compared to untreated VML injured muscles. As an acellular scaffold, biomimetic sponges provide a promising “off-the-shelf” clinical therapy for VML.

scholarly journals Biomimetic sponges improve muscle structure and function following volumetric muscle loss

2021 ◽  
Author(s):  
Gabriel Haas ◽  
Andrew Dunn ◽  
Josh Madsen ◽  
Peter Genovese ◽  
Hannah Chauvin ◽  
...  
Keyword(s):  
Structure And Function ◽  
Muscle Loss ◽  
Muscle Structure ◽  
Volumetric Muscle Loss ◽  
And Function

scholarly journals Decellularized Tissue for Muscle Regeneration

2018 ◽  
Vol 19 (8) ◽  
pp. 2392 ◽  
Author(s):  
Anna Urciuolo ◽  
Paolo De Coppi
Keyword(s):  
3D Structure ◽  
Future Application ◽  
Muscle Loss ◽  
Immune Rejection ◽  
Irreversible Loss ◽  
Volumetric Muscle Loss ◽  
Pathological Conditions ◽  
Xenogeneic Transplantation ◽  
Review Study ◽  
And Function

Several acquired or congenital pathological conditions can affect skeletal muscle leading to volumetric muscle loss (VML), i.e., an irreversible loss of muscle mass and function. Decellularized tissues are natural scaffolds derived from tissues or organs, in which the cellular and nuclear contents are eliminated, but the tridimensional (3D) structure and composition of the extracellular matrix (ECM) are preserved. Such scaffolds retain biological activity, are biocompatible and do not show immune rejection upon allogeneic or xenogeneic transplantation. An increase number of reports suggest that decellularized tissues/organs are promising candidates for clinical application in patients affected by VML. Here we explore the different strategies used to generate decellularized matrix and their therapeutic outcome when applied to treat VML conditions, both in patients and in animal models. The wide variety of VML models, source of tissue and methods of decellularization have led to discrepant results. Our review study evaluates the biological and clinical significance of reported studies, with the final aim to clarify the main aspects that should be taken into consideration for the future application of decellularized tissues in the treatment of VML conditions.

scholarly journals Photoreactive hydrogel stiffness influences volumetric muscle loss repair

2021 ◽  
Author(s):  
Ivan M Basurto ◽  
Juliana A Passipieri ◽  
Gregg M Gardner ◽  
Kathryn K Smith ◽  
Austin R Amacher ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
De Novo ◽  
Response Characteristic ◽  
Biochemical Properties ◽  
Muscle Loss ◽  
Post Injury ◽  
Chronic Inflammatory Response ◽  
Volumetric Muscle Loss ◽  
Tissue Characteristics ◽  
And Function

Volumetric muscle loss (VML) injuries are characterized by permanent loss of muscle mass, structure, and function. Hydrogel biomaterials provide an attractive platform for skeletal muscle tissue engineering due to the ability to easily modulate their biophysical and biochemical properties to match a range of tissue characteristics. In this work we successfully developed a mechanically tunable hyaluronic acid (HA) hydrogel system to investigate the influence of hydrogel stiffness on VML repair. HA was functionalized with photoreactive norbornene groups to create hydrogel networks that rapidly crosslink via thiol-ene click chemistry with tailored mechanics. Mechanical properties were controlled by modulating the amount of matrix metalloproteinase (MMP)-degradable peptide crosslinker to produce hydrogels with increasing elastic moduli of 1.1 ± 0.002, 3.0 ± 0.002, and 10.6 ± 0.006 kPa mimicking a relevant range of developing and mature muscle stiffnesses. Functional muscle recovery was assessed following implantation of the HA hydrogels by in situ photopolymerization into rat latissimus dorsi (LD) VML defects at 12 and 24 weeks post-injury. After 12 weeks, muscles treated with medium stiffness (3.0 kPa) hydrogels produced maximum isometric forces most similar to contralateral healthy LD muscles. This trend persisted at 24 weeks post-injury, suggestive of sustained functional recovery. Histological analysis revealed a significantly larger zone of regeneration with more de novo muscle fibers following implantation of medium stiffness hydrogels in VML-injured muscles compared to other experimental groups. Lower (low and medium) stiffness hydrogels also appeared to attenuate the chronic inflammatory response characteristic of VML injuries, displaying similar levels of macrophage infiltration and polarization to healthy muscle. Together these findings illustrate the importance of hydrogel mechanical properties in supporting functional repair of VML injuries.

scholarly journals Oxidative pathophysiology following volumetric muscle loss injury in a porcine model

2019 ◽  
Vol 126 (6) ◽  
pp. 1541-1549 ◽  
Author(s):  
Tony Chao ◽  
David M. Burmeister ◽  
Benjamin T. Corona ◽  
Sarah M. Greising
Keyword(s):  
Skeletal Muscle ◽  
Porcine Model ◽  
Fiber Type ◽  
Muscle Fibers ◽  
Oxidative Capacity ◽  
Mitochondrial Activity ◽  
Type I ◽  
Muscle Loss ◽  
Fiber Morphology ◽  
Volumetric Muscle Loss

Volumetric muscle loss (VML) occurs after severe orthopedic trauma and results in loss of muscle fibers and function that can leave patients permanently disabled. Although animals models of VML are useful to test possible therapeutic strategies, the pathophysiological characteristics of remaining skeletal muscle and changes in metabolism are not thoroughly understood. Herein, alterations of neuromuscular function, muscle fiber morphology, myosin heavy chain expression, and myofiber mitochondrial respiration were evaluated in an adult Yorkshire swine VML injury model. VML injured animals showed reduced peak isometric strength ( P < 0.05) and a shift toward smaller muscle fibers independent of fiber type ( P < 0.001). The muscle remaining after VML had a greater distribution of type I fibers and lower distribution of type II fibers ( P < 0.001). Skeletal muscle mitochondrial state 2 and state 3, reflecting complex I respiration, increased after injury ( P < 0.05) with a consistent trend to display higher oxygen flux per milligram of tissue. However, this was largely driven by increased mitochondrial content after VML which was associated with higher mitochondrial fission (FIS-1 protein levels). This study demonstrates an underlying perturbation of oxidative metabolism within the remaining musculature following surgical creation of an isolated, sterile VML injury in a porcine model that may be influential to the development of insidious pathophysiology and regenerative and rehabilitative therapies. NEW & NOTEWORTHY The natural injury sequela of volumetric muscle loss (VML) and associated pathophysiology of the remaining muscle is still incompletely understood. Herein we demonstrate a chronic muscle function deficit, with an increase in type I muscle fibers and parallel increase in oxidative capacity of remaining skeletal muscle. It is possible that the alteration in oxidative capacity after VML could largely be due to heightened mitochondrial activity and an increase in mitochondrial abundance.

Temporal changes in the muscle extracellular matrix due to volumetric muscle loss injury

2021 ◽  
pp. 1-14
Author(s):  
Daniel B. Hoffman ◽  
Christiana J. Raymond-Pope ◽  
Jacob R. Sorensen ◽  
Benjamin T. Corona ◽  
Sarah M. Greising
Keyword(s):  
Extracellular Matrix ◽  
Temporal Changes ◽  
Muscle Loss ◽  
Volumetric Muscle Loss
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