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Mul, Joram D.

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Mul

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Joram D.

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Mul, Joram D.
Author's Publications: search.filters.isAuthorOfPublication.77721dc3-7ff1-4219-8fb4-cb057939d124

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    Contraction stimulates muscle glucose uptake independent of atypical PKC
    (John Wiley & Sons, Ltd, 2015) Yu, Haiyan; Fujii, Nobuharu L; Toyoda, Taro; An, Ding; Farese, Robert V; Leitges, Michael; Hirshman, Michael F; Mul, Joram D.; Goodyear, Laurie
    Exercise increases skeletal muscle glucose uptake, but the underlying mechanisms are only partially understood. The atypical protein kinase C (PKC) isoforms λ and ζ (PKC-λ/ζ) have been shown to be necessary for insulin-, AICAR-, and metformin-stimulated glucose uptake in skeletal muscle, but not for treadmill exercise-stimulated muscle glucose uptake. To investigate if PKC-λ/ζ activity is required for contraction-stimulated muscle glucose uptake, we used mice with tibialis anterior muscle-specific overexpression of an empty vector (WT), wild-type PKC-ζ (PKC-ζWT), or an enzymatically inactive T410A-PKC-ζ mutant (PKC-ζT410A). We also studied skeletal muscle-specific PKC-λ knockout (MλKO) mice. Basal glucose uptake was similar between WT, PKC-ζWT, and PKC-ζT410A tibialis anterior muscles. In contrast, in situ contraction-stimulated glucose uptake was increased in PKC-ζT410A tibialis anterior muscles compared to WT or PKC-ζWT tibialis anterior muscles. Furthermore, in vitro contraction-stimulated glucose uptake was greater in soleus muscles of MλKO mice than WT controls. Thus, loss of PKC-λ/ζ activity increases contraction-stimulated muscle glucose uptake. These data clearly demonstrate that PKC-λ ζ activity is not necessary for contraction-stimulated glucose uptake.
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    Moderate voluntary exercise attenuates the metabolic syndrome in melanocortin-4 receptor-deficient rats showing central dopaminergic dysregulation☆
    (Elsevier, 2015) Obici, Silvana; Magrisso, I. Jack; Ghazarian, Armen S.; Shirazian, Alireza; Miller, Jonas R.; Loyd, Christine M.; Begg, Denovan P.; Krawczewski Carhuatanta, Kimberly A.; Haas, Michael K.; Davis, Jon F.; Woods, Stephen C.; Sandoval, Darleen A.; Seeley, Randy J.; Goodyear, Laurie; Pothos, Emmanuel N.; Mul, Joram D.
    Objective: Melanocortin-4 receptors (MC4Rs) are highly expressed by dopamine-secreting neurons of the mesolimbic tract, but their functional role has not been fully resolved. Voluntary wheel running (VWR) induces adaptations in the mesolimbic dopamine system and has a myriad of long-term beneficial effects on health. In the present experiments we asked whether MC4R function regulates the effects of VWR, and whether VWR ameliorates MC4R-associated symptoms of the metabolic syndrome. Methods: Electrically evoked dopamine release was measured in slice preparations from sedentary wild-type and MC4R-deficient Mc4rK314X (HOM) rats. VWR was assessed in wild-type and HOM rats, and in MC4R-deficient loxTBMc4r mice, wild-type mice body weight-matched to loxTBMc4r mice, and wild-type mice with intracerebroventricular administration of the MC4R antagonist SHU9119. Mesolimbic dopamine system function (gene/protein expression) and metabolic parameters were examined in wheel-running and sedentary wild-type and HOM rats. Results: Sedentary obese HOM rats had increased electrically evoked dopamine release in several ventral tegmental area (VTA) projection sites compared to wild-type controls. MC4R loss-of-function decreased VWR, and this was partially independent of body weight. HOM wheel-runners had attenuated markers of intracellular D1-type dopamine receptor signaling despite increased dopamine flux in the VTA. VWR increased and decreased ΔFosB levels in the nucleus accumbens (NAc) of wild-type and HOM runners, respectively. VWR improved metabolic parameters in wild-type wheel-runners. Finally, moderate voluntary exercise corrected many aspects of the metabolic syndrome in HOM runners. Conclusions: Central dopamine dysregulation during VWR reinforces the link between MC4R function and molecular and behavioral responding to rewards. The data also suggest that exercise can be a successful lifestyle intervention in MC4R-haploinsufficient individuals despite reduced positive reinforcement during exercise training.
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    Validity Assessment of 5 Day Repeated Forced-Swim Stress to Model Human Depression in Young-Adult C57BL/6J and BALB/cJ Mice
    (Society for Neuroscience, 2016) Mul, Joram D.; Zheng, Jia; Goodyear, Laurie
    The development of animal models with construct, face, and predictive validity to accurately model human depression has been a major challenge. One proposed rodent model is the 5 d repeated forced swim stress (5d-RFSS) paradigm, which progressively increases floating during individual swim sessions. The onset and persistence of this floating behavior has been anthropomorphically characterized as a measure of depression. This interpretation has been under debate because a progressive increase in floating over time may reflect an adaptive learned behavioral response promoting survival, and not depression (Molendijk and de Kloet, 2015). To assess construct and face validity, we applied 5d-RFSS to C57BL/6J and BALB/cJ mice, two mouse strains commonly used in neuropsychiatric research, and measured a combination of emotional, homeostatic, and psychomotor symptoms indicative of a depressive-like state. We also compared the efficacy of 5d-RFSS and chronic social defeat stress (CSDS), a validated depression model, to induce a depressive-like state in C57BL/6J mice. In both strains, 5d-RFSS progressively increased floating behavior that persisted for at least 4 weeks. 5d-RFSS did not alter sucrose preference, body weight, appetite, locomotor activity, anxiety-like behavior, or immobility behavior during a tail-suspension test compared with nonstressed controls. In contrast, CSDS altered several of these parameters, suggesting a depressive-like state. Finally, predictive validity was assessed using voluntary wheel running (VWR), a known antidepressant intervention. Four weeks of VWR after 5d-RFSS normalized floating behavior toward nonstressed levels. These observations suggest that 5d-RFSS has no construct or face validity but might have predictive validity to model human depression.