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To increase the amount of ATP, the cell transcribes the nuclear genes encoding mitochondrial proteins (NuGEMPs) which in turn promote the activity of the outer mitochondrial membrane (OMM) proteins, Mitofusin 1 and 2 (Mnf1/2) and the inner mitochondrial membrane (IMM) protein, Optic Atrophy Protein 1 (Opa1) ( On the other hand, under conditions of reduced energy demand or in the presence of dysfunctional mitochondria, such as during a sedentary lifestyle or aging, the fission mechanism (the removal of a mitochondria) is enhanced ( These mechanisms are also influenced by mitochondrial DNA (mtDNA)

In some embodiments, the invention encompasses contacting one or more NNMT inhibitors (such as a cation of Formula I or IA, or otherwise disclosed herein) is contacted with a cell expressing NNMT concurrently with one or more chemical entities (e.g., nicotinamide riboside, nicotinamide mononucleotide) that modulate intracellular NAD+ levels to provide muscular therapy

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