Post-transcriptional Regulation of De Novo Lipogenesis by mTORC1-S6K1-SRPK2 Signaling.

mTORC1 is a signal integrator and master regulator of cellular anabolic processes linked to cell growth and survival. Here, we demonstrate that mTORC1 promotes lipid biogenesis via SRPK2, a key regulator of RNA-binding SR proteins. mTORC1-activated S6K1 phosphorylates SRPK2 at Ser494, which primes Ser497 phosphorylation by CK1. These phosphorylation events promote SRPK2 nuclear translocation and phosphorylation of SR proteins. Genome-wide transcriptome analysis reveals that lipid biosynthetic enzymes are among the downstream targets of mTORC1-SRPK2 signaling. Mechanistically, SRPK2 promotes SR protein binding to U1-70K to induce splicing of lipogenic pre-mRNAs. Inhibition of this signaling pathway leads to intron retention of lipogenic genes, which triggers nonsense-mediated mRNA decay. Genetic or pharmacological inhibition of SRPK2 blunts de novo lipid synthesis, thereby suppressing cell growth. These results thus reveal a novel role of mTORC1-SRPK2 signaling in post-transcriptional regulation of lipid metabolism and demonstrate that SRPK2 is a potential therapeutic target for mTORC1-driven metabolic disorders.

mTORC1 Promotes Metabolic Reprogramming by the Suppression of GSK3-Dependent Foxk1 Phosphorylation.

The mammalian Target of Rapamycin Complex 1 (mTORC1)-signaling system plays a critical role in the maintenance of cellular homeostasis by sensing and integrating multiple extracellular and intracellular cues. Therefore, uncovering the effectors of mTORC1 signaling is pivotal to understanding its pathophysiological effects. Here we report that the transcription factor forkhead/winged helix family k1 (Foxk1) is a mediator of mTORC1-regulated gene expression. Surprisingly, Foxk1 phosphorylation is increased upon mTORC1 suppression, which elicits a 14-3-3 interaction, a reduction of DNA binding, and nuclear exclusion. Mechanistically, this occurs by mTORC1-dependent suppression of nuclear signaling by the Foxk1 kinase, Gsk3. This pathway then regulates the expression of multiple genes associated with glycolysis and downstream anabolic pathways directly modulated by Foxk1 and/or by Foxk1-regulated expression of Hif-1α. Thus, Foxk1 mediates mTORC1-driven metabolic rewiring, and it is likely to be critical for metabolic diseases where improper mTORC1 signaling plays an important role.

Effect of a static calf muscle-tendon unit stretching program on ankle dorsiflexion range of motion of older women.

BACKGROUND AND PURPOSE: While there has been considerable research on stretching, a paucity of research has focused on stretching of the calf muscle-tendon unit (MTU) in older women. Because limited ankle dorsiflexion range of motion (ROM) is associated with gait abnormalities and increases the risk of falls in the elderly, we investigated the effect of static stretching on flexibility of the calf MTU of healthy elderly adults. METHODS: Twenty healthy female volunteers, 76 to 91 years of age, were recruited from Linda Valley Villa, an independent living center. Subjects performed a static stretching program 5 days a week for 6 weeks. Passive ankle dorsiflexion ROM was taken prior to beginning the stretching program and 3 days after the last stretching day. RESULTS: Mean increase in passive ankle dorsiflexion ROM was 12.3 degrees (SD= 4.4 degrees ) (p < .001). CONCLUSION: A 6-week stretching program is capable of provoking a significant increase in ankle dorsiflexion ROM for elderly women.

Middle and lower trapezius strengthening for the management of lateral epicondylalgia: a case report.

STUDY DESIGN: Case report. BACKGROUND: Addressing weakness of the shoulder region, especially the rotator cuff and scapular musculature, is often suggested clinically for the treatment of individuals with lateral epicondylalgia. However, to our knowledge, the clinical effectiveness of this approach has not been established. CASE DESCRIPTION: The patient was a 54-year-old woman with a 5-month history of right lateral elbow pain, whose symptoms were reproduced with clinical tests typically used to diagnose lateral elbow tendinopathy. The patient also demonstrated weakness in her middle and lower trapezius muscles, and the medial border of her scapula, measured with a tape measure, was 11 cm lateral from the spinous processes of the thoracic spine with the patient standing in relaxed stance. Based on improved grip strength and reduced associated elbow pain when tested with the scapula manually corrected in a more adducted position, treatment focused solely on strengthening of the middle and lower trapezius muscles over a 10-week period. OUTCOMES: Following the intervention, the patient presented with improved scapular position, with the medial border of the scapula being 9 cm lateral to the midthoracic spine. The patient's middle and lower trapezius strength improved from 3+/5 and 4-/5, respectively, to 5/5, and her grip strength from 26.1 to 42.2 kg. The patient's scores on the Disabilities of the Arm, Shoulder and Hand questionnaire also improved from 44.2 at the initial evaluation to 0 at the completion of therapy, with the patient being able to perform all of her daily activities in a pain-free manner. DISCUSSION: The results of this case report suggest that assessment and treatment of scapular musculature warrant consideration in the management of individuals with lateral epicondylalgia. LEVEL OF EVIDENCE: Therapy, level 4.