Immunology Guides Skeletal Muscle Regeneration

Abstract

Soft tissue trauma of skeletal muscle is one of the most common side effects in surgery. Muscle injuries are not only caused by accident-related injuries but can also be of an iatrogenic nature as they occur during surgical interventions when the anatomical region of interest is exposed. If the extent of trauma surpasses the intrinsic regenerative capacities, signs of fatty degeneration and formation of fibrotic scar tissue can occur, and, consequentially, muscle function deteriorates or is diminished. Despite research efforts to investigate the physiological healing cascade following trauma, our understanding of the early onset of healing and how it potentially determines success or failure is still only fragmentary. This review focuses on the initial physiological pathways following skeletal muscle trauma in comparison to bone and tendon trauma and what conclusions can be drawn from new scientific insights for the development of novel therapeutic strategies. Strategies to support regeneration of muscle tissue after injury are scarce, even though muscle trauma has a high incidence. Based on tissue specific differences, possible clinical treatment options such as local immune-modulatory and cell therapeutic approaches are suggested that aim to support the endogenous regenerative potential of injured muscle tissues.

Biomaterials Functionalized with MSC Secreted Extracellular Vesicles and Soluble Factors for Tissue Regeneration

“…Scar formation can occur after muscle injury caused by trauma or surgical interventions, [ 228 ] and the MSC secretome can potentially promote muscle regeneration. For example, in a model of volumetric muscle loss, MSC‐CM delivered in a collagen hydrogel exhibited immunomodulatory activity and led to enhanced muscle regeneration.…”

Interactions between Muscle and Bone—Where Physics Meets Biology

“…A list of genes (selected by the authors using educated guesses) that are upregulated after respective time points is provided in Table 1; complete lists can be found in the article. Interestingly, the early genes such as proinflammatory cytokines IL-1b, IL-6, IL-8, the toll-like receptor 4 (TLR4) ligands serum amyloid A1 (SAA1) and SAA2, CYR61/CCN1, connective tissue growth factor (CTGF/CCN2), angiopoietin-like 4 (ANGPTL4) and ANGPTL2 very closely resemble genes that are also relevant in the initial phase of osteogenic differentiation and contribute to angiogenesis in fracture healing [91][92][93]. Already after 2h, the mRNAs encoding proinflammatory genes have gone back to basal levels.…”

“…Cells of both the innate and the adaptive immune system are intricately involved in the efficient regeneration in both muscle and bone [93,137].…”

Cell therapy to improve regeneration of skeletal muscle injuries

“…However, experimental evidence suggests that an early and short‐term use of such anti‐inflammatory drugs only moderately reduces the extent of muscle damage, while persistent use of NSAIDs negatively influences muscle regeneration and contractile function . This could be due to the broad effects of these drugs on the immune system, potentially interfering with its central role in the progression of the healing process or final resolution of muscle injury . Furthermore, a study by Rahusen et al .…”

“…40 This could be due to the broad effects of these drugs on the immune system, potentially interfering with its central role in the progression of the healing process or final resolution of muscle injury. 41,42 Furthermore, a study by Rahusen et al questioned the exclusivity of using NSAIDs because they did not demonstrate a superior effect than do low-cost painkillers and analgesics. 43 Despite lack of supportive evidence from human clinical trials and known negative side effects, 44 NSAIDs continue to be a popular medication among athletes, and further investigation is needed to elucidate the local effects of these drugs on the healing cascade of skeletal muscles.…”