Skeletal muscle injury resulting in tissue loss poses unique challenges for surgical repair. Despite the regenerative potential of skeletal muscle, if a significant amount of tissue is lost, skeletal myofibers will not grow to fill the injured area completely. Prior work in our lab has shown the potential to fill the void with an extracellular matrix (ECM) scaffold, resulting in restoration of morphology, but not functional recovery. To improve the functional outcome of the injured muscle, a muscle-derived ECM was implanted into a 1 x 1 cm(2), full-thickness defect in the lateral gastrocnemius (LGAS) of Lewis rats. Seven days later, bone-marrow-derived mesenchymal stem cells (MSCs) were injected directly into the implanted ECM. Partial functional recovery occurred over the course of 42 days when the LGAS was repaired with an MSC-seeded ECM producing 85.4 +/- 3.6% of the contralateral LGAS. This was significantly higher than earlier recovery time points (p < 0.05). The specific tension returned to 94 +/- 9% of the contralateral limb. The implanted MSC-seeded ECM had more blood vessels and regenerating skeletal myofibers than the ECM without cells (p < 0.05). The data suggest that the repair of a skeletal muscle defect injury by the implantation of a muscle-derived ECM seeded with MSCs can improve functional recovery after 42 days.
The loss of a portion of skeletal muscle poses a unique challenge for the normal regeneration of muscle tissue. A transection injury with tissue loss will not heal due to the gap between muscle segments. A damage model was developed by removing a portion of the lateral gastrocnemius (GAS) of Sprague-Dawley rats. Maximal isometric, tetanic tension (P(o)) was measured after the removal of either a small defect (0.5 x 1.0 cm) or a large defect (1.0 x 1.0 cm) piece of the GAS. In situ P(o) immediately after creation of the defect was 88.3 +/- 2.0% of the nonoperated contralateral GAS force for small defect and 76.9 +/- 3.2% of control for large defect. No functional recovery occurred in either group over the course of 28 days. To enhance recovery, a homologous, decellularized, muscle extracellular matrix (ECM) was implanted into the 1 x 1 cm defect of the lateral GAS of Lewis rats. After 42 days, growth of blood vessels and myofibers into the ECM was apparent, but no restoration of P(o) occurred. These data demonstrate the ability of the ECM to support muscle and blood vessel regeneration, but full recovery of function does not occur after 42 days.
The regenerative response of skeletal muscle to mechanically induced damage is impaired with age. Previous work in our laboratory suggests this may result from higher proinflammatory signaling in aging muscle at rest and/or a greater inflammatory response to damage. We, therefore, assessed skeletal muscle proinflammatory signaling at rest and 24 h after unaccustomed, loaded knee extension contractions that induced modest muscle damage (72% increase in serum creatine kinase) in a cohort of 87 adults across three age groups (AGE40, AGE61, and AGE76). Vastus lateralis muscle gene expression and protein cell signaling of the IL-6 and TNF-α pathways were determined by quantitative PCR and immunoblot analysis. For in vitro studies, cell signaling and fusion capacities were compared among primary myoblasts from young (AGE28) and old (AGE64) donors treated with TNF-α. Muscle expression was higher (1.5- to 2.1-fold) in AGE76 and AGE61 relative to AGE40 for several genes involved in IL-6, TNF-α, and TNF-like weak inducer of apoptosis signaling. Indexes of activation for the proinflammatory transcription factors signal transducer and activator of transcription-3 and NF-κB were highest in AGE76. Resistance loading reduced gene expression of IL-6 receptor, muscle RING finger 1, and atrogin-1, and increased TNF-like weak inducer of apoptosis receptor expression. Donor myoblasts from AGE64 showed impaired differentiation and fusion in standard media and greater NF-κB activation in response to TNF-α treatment (compared with AGE28). We show for the first time that human aging is associated with muscle inflammation susceptibility (i.e., higher basal state of proinflammatory signaling) that is present in both tissue and isolated myogenic cells and likely contributes to the impaired regenerative capacity of skeletal muscle in the older population.
Age-related muscle loss (sarcopenia) is a major clinical problem affecting both men and women - accompanied by muscle weakness, dysfunction, disability, and impaired quality of life. Current definitions of sarcopenia do not fully encompass the age-related changes in skeletal muscle. We therefore examined the influence of aging and sex on elements of skeletal muscle health using a thorough histopathological analysis of myocellular aging and assessments of neuromuscular performance. Two-hundred and twenty-one untrained males and females were separated into four age cohorts [mean age 25 y (n = 47), 37 y (n = 79), 61 y (n = 51), and 72 y (n = 44)]. Total (-12%), leg (-17%), and arm (-21%) lean mass were lower in both 61 y and 72 y than in 25 y or 37 y (P < 0.05). Knee extensor strength (-34%) and power (-43%) were lower (P < 0.05) in the older two groups, and explosive sit-to-stand power was lower by 37 y (P < 0.05). At the histological/myocellular level, type IIx atrophy was noted by 37 y and type IIa atrophy by 61 y (P < 0.05). These effects were driven by females, noted by substantial and progressive type IIa and IIx atrophy across age. Aged female muscle displayed greater within-type myofiber size heterogeneity and marked type I myofiber grouping (~5-fold greater) compared to males. These findings suggest the predominant mechanisms leading to whole muscle atrophy differ between aging males and females: myofiber atrophy in females vs. myofiber loss in males. Future studies will be important to better understand the mechanisms underlying sex differences in myocellular aging and optimize exercise prescriptions and adjunctive treatments to mitigate or reverse age-related changes.
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