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Principal Investigator: Marco Brotto
Organization: UNIVERSITY OF SOUTH FLORIDA
Fiscal Year: 2020
Award: $409,106
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
Project Summary
Diabetes is a leading cause of death in the US and worldwide with deleterious consequences to the
musculoskeletal system. Regardless of glycemic control, diabetes in skeletal muscle manifests with altered
metabolism leading to progressive skeletal muscle loss, functional decline, fast-type myofiber atrophy,
increased susceptibility to injury and impaired regeneration. The proposal we develop understanding for the
direct causal phenomenon associated with altered metabolism and increased risk to skeletal muscle in
diabetes. We have identified that diabetes causes significant elevation in muscle NADH levels along with
depleted NAD+ reserves. This phenomenon directly associates with decreased muscle function and damage.
Based on our preliminary studies and expertise in the area of pyridine nucleotides and metabolic regulation, we
hypothesize that decreased NAD/NADH ratio in the diabetic skeletal muscle leads to decline in muscle
function, and activation of nicotinamide phosphoribosyl transferase (Nampt) is protective. The major objective
is to develop Nampt activators to protect skeletal muscles from diabetes and other metabolic-related
syndromes. For this, we propose two specific aims. Under Specific Aim 1A, we will rescue insulin resistance in
diabetic skeletal muscle with P7C3. We will utilize diabetic mouse model to identify decreased muscle activity
and strength and the relevance of Nampt, NAD/NADH ratio for improvement of function. The experimental
approach will include functional, biochemical and molecular measurements. These experiments will establish
the fundamental role of NAD/NADH in diabetic skeletal muscle. Specific Aim 1B will develop the innovative
skeletal muscle targeting P7C3 nano particle drug delivery system. The Carnitine-P7C3 particle will allow
higher therapeutic efficacy for in vivo and in vitro delivery. Under Specific Aim 2A we will investigate the
mechanistic basis of P7C3 against diabetic complications in skeletal muscle. The signaling pathway involving
Nampt-HNF1β-PPARα will be elucidated using muscle specific knock out mouse models for HNF1βflox along
with HSAcre mice to evaluate the chief role of hepatocyte nuclear factor 1-β (HNF1β) as a new functional
metabolic modulator in skeletal muscles. Finally, in Sub aim 2B we will investigate the molecular
pharmacology of Nampt and its specificity for targeting and identification of SIRT1, HNF1β along with lipid
signaling mediators involved in muscle protection. Overall, completion of the project will determine the causal
role of Nampt in diabetic skeletal muscle and unravel novel mechanisms with new targets HNF1β that co-
orchestrate with Nampt to optimally regulate metabolism in skeletal muscle.
Terms: <3-Pyridinecarboxamide><9-azafluorene><Absolute ethanol><Adult-Onset Diabetes Mellitus><Anti-diabetic Agents><Antidiabetic Agents><Antidiabetic Drugs><Area><Atrophic><Atrophy><Automobile Driving><Autoregulation><Biochemical><Carbazoles><Carnitine><Cause of Death><Cell Communication and Signaling><Cell Signaling><Cell Survival><Cell Viability><Complications of Diabetes Mellitus><Data><Diabetes Complications><Diabetes Mellitus><Diabetes-Related Complications><Diabetic Complications><Diabetic mouse><Diagnosis><Diet><Dihydronicotinamide Adenine Dinucleotide><Diphosphopyridine Nucleotide><Disease><Disorder><Drug Delivery><Drug Delivery Systems><ETOH><Economic Burden><Encapsulated><Energy Expenditure><Energy Metabolism><Enzyme Gene><Enzymes><Equilibrium><Ethanol><Ethyl Alcohol><Generalized Growth><Genes><Glycolates><Goals><Grain Alcohol><Growth><HNF-1 protein><Homeostasis><Humulin R><Impairment><In Vitro><Incidence><Injury><Insulin><Insulin Resistance><Intermediary Metabolism><Intracellular Communication and Signaling><KO mice><Ketosis-Resistant Diabetes Mellitus><Knock-out Mice><Knockout Mice><Link><Lipids><Maturity-Onset Diabetes Mellitus><Measurement><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Methylcarbinol><Mice><Mice Mammals><Molecular><Murine><Mus><Muscle><Muscle Tissue><Muscle function><Musculoskeletal><Musculoskeletal System><NIDDM><Nadide><Natural regeneration><New Agents><Niacinamide><Nicotinamide><Nicotinamide adenine dinucleotide><Nicotinamide-Adenine Dinucleotide><Nicotinamidum><Nicotinic acid amide><Nicotylamide><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Novolin R><Null Mouse><Obesity><Outcome><Oxidation-Reduction><PPAR alpha><PPAR-α><PPARalpha><PPARα><Pathway interactions><Pellagra-Preventing Factor><Peroxisome Proliferator-Activated Receptor alpha><Peroxisome Proliferator-Activated Receptor α><Pharmacology><Physiological Homeostasis><Play><Predisposition><Redox><Regeneration><Regular Insulin><Regulation><Risk><Role><SIRT1><SIRT1 gene><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Sirtuin 1><Skeletal Muscle><Skeletal muscle injury><Slow-Onset Diabetes Mellitus><Specificity><Stable Diabetes Mellitus><Structure><Susceptibility><Syndrome><T2 DM><T2D><T2DM><Testing><Thesaurismosis><Tissue Growth><Transferase><Transferase Gene><Treatment Efficacy><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Vitamin B 3><Vitamin B3><Vitamin PP><Voluntary Muscle><adiposity><adult onset diabetes><anti-diabetic><anti-diabetic drugs><antidiabetic><balance><balance function><base><biodegradable polymer><biological signal transduction><bioresorbable polymer><blood glucose regulation><cardiac disease risk><cardiac disorder risk><corpulence><corpulency><corpulentia><decline in function><decline in functional status><decreased muscle strength><degradable polymer><diabetes><diabetes mouse model><diabetic><dibenzopyrrole><dietary><diphenylenimine><driving><dynapenia><experiment><experimental research><experimental study><fat metabolism><fatty acid oxidation><function improvement><functional decline><functional improvement><functional status decline><glucose control><glucose homeostasis><glucose metabolism><glucose regulation><glucose tolerance><glycemic control><glycolic acid><heart disease risk><heart disorder risk><hepatic nuclear factor 1><hepatocyte nuclear factor 1><improved><in vivo><injuries><innovate><innovation><innovative><insight><insulin resistant><intervention efficacy><ketosis resistant diabetes><lipid metabolism><liver specific transcription factor LF-B1><locomotor system><low muscle strength><maturity onset diabetes><metabolism disorder><mouse model><murine model><muscle strength decline><muscular><nano particle drug><nanoparticle drug><novel><nuclear protein LF-B1><obese><obese people><obese person><obese population><ontogeny><oxidation><oxidation reduction reaction><particle><pathway><prevent><preventing><pyridine nucleotide><reduced muscle strength><regenerate><skeletal muscle atrophy><skeletal muscle breakdown><skeletal muscle loss><skeletal muscle metabolism><skeletal muscle protein loss><skeletal muscle protein metabolism><skeletal muscle wasting><social role><therapeutic efficacy><therapeutically effective><therapy efficacy><transcription factor APF><transcription factor HNF1><transcription factor HP1><transcription factor LFB1><type 2 DM><type II DM><type two diabetes>