Longtime Outcome After Intraosseous Application of Autologous Mesenchymal Stromal Cells in Pediatric Patients and Young Adults with Avascular Necrosis After Steroid or Chemotherapy.

Avascular necrosis (AVN) is a severe complication of immunosuppressant therapy or chemotherapy. A beneficial AVN therapy with core decompression (CD) and intraosseous infusion of mesenchymal stromal cells (MSCs) has been described in adult patients, but there are only few data on MSC applications in pediatric and young adult patients (PYAP). Between 2006 and 2015, 14 AVN lesions of 10 PYAP (6 females) with a median age of 16.9 years (range 8.5-25.8 years) received CD and intraosseous application of autologous MSCs. Data of these patients were analyzed regarding efficacy, safety, and feasibility of this procedure as AVN therapy and compared with a control group of 13 AVN lesions of 11 PYAP (5 females) with a median age of 17.9 years (range 13.5-27.5 years) who received CD only. During the follow-up analysis [MSC group: median 3.1 (1.6-5.8) years after CD; CD group: median 2.0 (1.5-8.5) years after CD], relative lesion sizes (as assessed by magnetic resonance imaging) compared with the initial lesion volume, were significantly lower (P < 0.05) in the MSC group (volume reduction to a median of 18.5%) when compared with the CD group (58.0%). One lesion in the MSC group comprised a complete remission. Size progression was not observed in either group. Clinical improvement (pain, mobility) was not significantly different between the two groups. None of the patients experienced treatment-related adverse effects. CD and additional MSC application was regarded safe, effective, feasible, and superior in reducing the lesion size when compared with CD only. Prospective, randomized clinical trials are needed to further evaluate these findings.

ATP citrate lyase improves mitochondrial function in skeletal muscle.

Mitochondrial dysfunction is associated with skeletal muscle pathology, including cachexia, sarcopenia, and the muscular dystrophies. ATP citrate lyase (ACL) is a cytosolic enzyme that catalyzes mitochondria-derived citrate into oxaloacetate and acetyl-CoA. Here we report that activation of ACL in skeletal muscle results in improved mitochondrial function. IGF1 induces activation of ACL in an AKT-dependent fashion. This results in an increase in cardiolipin, thus increasing critical mitochondrial complexes and supercomplex activity, and a resultant increase in oxygen consumption and cellular ATP levels. Conversely, knockdown of ACL in myotubes not only reduces mitochondrial complex I, IV, and V activity but also blocks IGF1-induced increases in oxygen consumption. In vivo, ACL activity is associated with increased ATP. Activation of this IGF1/ACL/cardiolipin pathway combines anabolic signaling with induction of mechanisms needed to provide required ATP.

Gαi2 signaling promotes skeletal muscle hypertrophy, myoblast differentiation, and muscle regeneration.

Skeletal muscle atrophy results in loss of strength and an increased risk of mortality. We found that lysophosphatidic acid, which activates a G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor, stimulated skeletal muscle hypertrophy through activation of Gα(i2). Expression of a constitutively active mutant of Gα(i2) stimulated myotube growth and differentiation, effects that required the transcription factor NFAT (nuclear factor of activated T cells) and protein kinase C. In addition, expression of the constitutively active Gα(i2) mutant inhibited atrophy caused by the cachectic cytokine TNFα (tumor necrosis factor-α) by blocking an increase in the abundance of the mRNA encoding the E3 ubiquitin ligase MuRF1 (muscle ring finger 1). Gα(i2) activation also enhanced muscle regeneration and caused a switch to oxidative fibers. Our study thus identifies a pathway that promotes skeletal muscle hypertrophy and differentiation and demonstrates that Gα(i2)-induced signaling can act as a counterbalance to MuRF1-mediated atrophy, indicating that receptors that act through Gα(i2) might represent potential targets for preventing skeletal muscle wasting.