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Volumetric muscle loss (VML), usually occurring following traumatic injury, results in a composite loss of muscle mass. These injuries manifest as decreased strength and functional impairments. Clinically, these injuries often heal with fibrosis, as opposed to skeletal muscle regeneration. This study examines the healing patterns of a skeletal muscle following VML in a murine model. Eight-week old male C57BL/6J mice used in the study underwent either bilateral VML injury or cryoinjury, a widely used model known to induce skeletal muscle regeneration. Skeletal muscle was harvested at 2 and 4 weeks following injury and subjected to histological analysis. H&E staining demonstrated skeletal muscle regeneration following cryoinjury, but not VML, at either timepoint post-injury. Additionally, samples were analyzed using a wound-healing PCR array to identify differentially regulated genes of interest in VML and cryoinjury, as compared to noninjured controls. The gene array data further demonstrated prolonged inflammation and increased pro-fibrotic activity in the VML injured muscles, as compared to cryoinjury. In addition, IGF1, a known myogenic factor, was significantly decreased following VML, as compared to cryoinjury, in both ELISA and PCR. This study offers an insight into the pathophysiology of VML injury and reveals a gene profile of a nonregenerating skeletal muscle.

No abstract

Skeletal muscle maintenance is a dynamic process and undergoes constant repair and regeneration. However, skeletal muscle regenerative capacity declines in obesity. In this review, we focus on obesity-associated changes in inflammation, metabolism, and impaired insulin signaling, which are pathologically dysregulated and ultimately result in a loss of muscle mass and function. In addition, we examine the relationships between skeletal muscle, liver, and visceral adipose tissue in an obese state.

Volumetric muscle loss (VML) is a segmental loss of skeletal muscle which commonly heals with fibrosis, minimal muscle regeneration, and loss of muscle strength. Treatment options for these wounds which promote functional recovery are currently lacking. This study was designed to investigate whether the collagen‐GAG scaffold (CGS) promotes functional muscle recovery following VML. A total of 66 C57/Bl6 mice were used in a three‐stage experiment. First, 24 animals were split into three groups which underwent sham injury or unilateral quadriceps VML injury with or without CGS implantation. Two weeks post‐surgery, muscle was harvested for histological and gene expression analysis. In the second stage, 18 mice underwent bilateral quadriceps VML injury, followed by weekly functional testing using a treadmill. In the third stage, 24 mice underwent sham or bilateral quadriceps VML injury with or without CGS implantation, with tissue harvested six weeks post‐surgery for histological and gene expression analysis. VML mice treated with CGS demonstrated increased remnant fiber hypertrophy versus both the VML with no CGS and uninjured groups. Both VML groups showed greater muscle fiber hypertrophy than non‐injured muscle. This phenomenon was still evident in the longer‐term experiment. The gene array indicated that the CGS promoted upregulation of factors involved in promoting wound healing and regeneration. In terms of functional improvement, the VML mice treated with CGS ran at higher maximum speeds than VML without CGS. A CGS was shown to enhance muscle hypertrophy in response to VML injury with a resultant improvement in functional performance. A gene array highlighted increased gene expression of multiple growth factors following CGS implantation. This suggests that implantation of a CGS could be a promising treatment for VML wounds.

Foam-mediated external volume expansion improves flap survival in obese diabetic mice. This procedure may allow for improved clinical rates of flap survival in high-risk patients.

Obesity leads to a loss of muscle mass and impaired muscle regeneration. In obese individuals, pathologically elevated levels of prolyl hydroxylase domain enzyme 2 (PHD2) limit skeletal muscle hypoxia-inducible factor-1 alpha and vascular endothelial growth factor (VEGF) expression. Loss of local VEGF may further impair skeletal muscle regeneration. We hypothesized that PHD2 inhibition would restore vigorous muscle regeneration in a murine model of obesity. Adult (22-week-old) male mice were fed either a high-fat diet (HFD), with 60% of calories derived from fat, or a regular diet (RD), with 10% of calories derived from fat, for 16 weeks. On day 5 following cryoinjury to the tibialis anterior muscle, newly regenerated muscle fiber cross-sectional areas were significantly smaller in mice fed an HFD as compared to RD, indicating an impaired regenerative response. Cryoinjured gastrocnemius muscles of HFD mice also showed elevated PHD2 levels (twofold higher) and reduced VEGF levels (twofold lower) as compared to RD. Dimethyloxalylglycine, a cell permeable competitive inhibitor of PHD2, restored VEGF levels and significantly improved regenerating myofiber size in cryoinjured mice fed an HFD. We conclude that pathologically increased PHD2 in the obese state drives impairments in muscle regeneration, in part by blunting VEGF production. Inhibition of PHD2 over activity in the obese state normalizes VEGF levels and restores muscle regenerative potential.

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