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Quiescent stem cells are activated in response to a mechanical or chemical injury to their tissue niche. Activated cells rapidly generate a heterogeneous progenitor population that regenerates the damaged tissues. While the transcriptional cadence that generates heterogeneity is known, the metabolic pathways influencing the transcriptional machinery to establish a heterogeneous progenitor population remains unclear. Here, we describe a novel pathway downstream of mitochondrial glutamine metabolism that confers stem cell heterogeneity and establishes differentiation competence by countering post-mitotic self-renewal machinery. We discovered that mitochondrial glutamine metabolism induces CBP/EP300-dependent acetylation of stem cell-specific kinase, PAS domain-containing kinase (PASK), resulting in its release from cytoplasmic granules and subsequent nuclear migration. In the nucleus, PASK catalytically outcompetes mitotic WDR5-anaphase-promoting complex/cyclosome (APC/C) interaction resulting in the loss of post-mitotic Pax7 expression and exit from self-renewal. In concordance with these findings, genetic or pharmacological inhibition of PASK or glutamine metabolism upregulated Pax7 expression, reduced stem cell heterogeneity , and blocked myogenesis in vitro and muscle regeneration in mice. These results explain a mechanism whereby stem cells co-opt the proliferative functions of glutamine metabolism to generate transcriptional heterogeneity and establish differentiation competence by countering the mitotic self-renewal network via nuclear PASK., Competing Interests: MX, CW, GM, BK, DC, LY, SM, SD, EM, PS, AD, MG, LB, RS, CK No competing interests declared, (© 2023, Xiao, Wu, Meek et al.)

The internal derangement of the temporomandibular joint (TMJ) represents 8% of all cases of temporomandibular disorders (TMD) posing difficulties to establish an accurate diagnosis and treatment because of its low prevalence. This article presents the case of an 18-year-old Caucasian female patient who came to our Orofacial Pain and TMD Outpatient Service with complaints of intense pain on the right TMJ and limitation of mouth opening (maximum interincisal opening of 29 mm) with deviation to right, which she had been experiencing for the past 3 years. After a detailed clinical interview, a diagnosis hypothesis of nonreducing disc displacement with mouth opening limitation was established. The proposed treatment consisted of intra-joint infiltration with anesthetic in the right TMJ followed by jaw manipulation to recapture the articular disc, which was impeding the complete translation movement of the affected TMJ. After jaw manipulation, a new evaluation was done and showed the re-establishment of jaw dynamics with mouth opening and closing without deviation to the right side, clicking, opening limitation or pain. The patient was followed up at 6 months intervals. Two years after treatment, the patient was reevaluated and her mandibular range of motion without aid increased to 54 mm with no clicking, deviation to right, trismus or pain on the TMJ, indicating success of the treatment approach without recurrence of the pathology.