Perinatal versus adult loss of ULK1 and ULK2 distinctly influences cardiac autophagy and function.

Impairments in macroautophagy/autophagy, which degrades dysfunctional organelles as well as long-lived and aggregate proteins, are associated with several cardiomyopathies; however, the regulation of cardiac autophagy remains insufficiently understood. In this regard, ULK1 and ULK2 are thought to play primarily redundant roles in autophagy initiation, but whether their function is developmentally determined, potentially having an impact on cardiac integrity and function remains unknown. Here, we demonstrate that perinatal loss of ULK1 or ULK2 in cardiomyocytes (cU1-KO and cU2-KO mice, respectively) enhances basal autophagy without altering autophagy machinery content while preserving cardiac function. This increased basal autophagy is dependent on the remaining ULK protein given that perinatal loss of both ULK1 and ULK2 in cU1/2-DKO mice impaired autophagy causing age-related cardiomyopathy and reduced survival. Conversely, adult loss of cardiac ULK1, but not of ULK2 (i.e., icU1-KO and icU2-KO mice, respectively), led to a rapidly developing cardiomyopathy, heart failure and early death. icU1-KO mice had impaired autophagy with robust deficits in mitochondrial respiration and ATP synthesis. Trehalose ameliorated autophagy impairments in icU1-KO hearts but did not delay cardiac dysfunction suggesting that ULK1 plays other critical, autophagy-independent, functions in the adult heart. Collectively, these results indicate that cardiac ULK1 and ULK2 are functionally redundant in the developing heart, while ULK1 assumes a more unique, prominent role in the adult heart.Abbreviations: ATG4: autophagy related 4, cysteine peptidase; ATG5: autophagy related 5; ATG7: autophagy related 7; ATG9: autophagy related 9; ATG13: autophagy related 13; CYCS: Cytochrome C; DNM1L, dynamin 1-like; MAP1LC3A: microtubule-associated protein 1 light chain 3 alpha; MAP1LC3B: microtubule-associated protein 1 light chain 3 beta; MFN1: mitofusin 1; MFN2: mitofusin 2; MT-CO1: mitochondrially encoded cytochrome c oxidase I; MYH: myosin, heavy polypeptide; NBR1: NBR1 autophagy cargo receptor; NDUFA9: NADH:ubiquinone oxidoreductase subunit A9; OPA1: OPA1, mitochondrial dynamin like GTPase; PPARGC1A, peroxisome proliferator activated receptor, gamma, coactivator 1 alpha; SDHA: succinate dehydrogenase complex, subunit A, flavoprotein (Fp); SQSTM1: sequestosome 1; ULK1: unc-51 like kinase 1; ULK2: unc-51 like kinase 2; UQCRC1: ubiquinol-cytochrome c reductase core protein 1.

Case series of vestibular schwannoma patients with no asymmetry in hearing.

OBJECTIVE: (1) Describe the presenting symptoms and tumor characteristics of patients who are diagnosed with a vestibular schwannoma (VS) with normal hearing or symmetric hearing loss, and (2) report the prospective growth and treatment of each tumor. METHODS: This is a retrospective cohort study of acoustic neuroma patients who were found to have a VS and normal or symmetric hearing loss at a single tertiary care academic center from 1999 to 2012. Medical records were reviewed collecting the following information: patient demographics, symptoms, MRI characteristics, and treatment modality. RESULTS: 15/195 (7.7%) patients met criteria for the study. Dizziness was the most common presenting symptom occurring in 9 subjects (60%), followed by headache in 6 (40%), vision changes in 5 (33%), tinnitus in 5 (33%), and unilateral hearing loss in 1 (7%). The average tumor size was 1.07 cm (range 0.3-2.2 cm). Eight (53%) patients presented with intracanalicular tumors. Growth was observed in 6 subjects (40%) with average growth rate in those who exhibited mean growth of 1.8 mm per year. Treatment consisted of surgical removal in 4 cases (27%), gamma knife therapy in 1 (7%), and observation or loss to follow-up in 10 (66%). CONCLUSIONS: The incidence of VS with normal hearing was 7.7% Patients with VSs who do not exhibit unilateral hearing loss present most commonly with dizziness. Most of our patients had small, intracanalicular tumors with the largest tumor measuring 2.2 cm in greatest dimension. Of those who were managed conservatively with repeat imaging and observation, most showed tumor growth.