There Is Not Enough Evidence to Conclude That Nicotinamide Adenine Dinucleotide

(NAD) Helps Decelerate the Progress of Muscle Degeneration

Neuromuscular diseases and disorders are acquired or inherited (genetic) perilous

conditions that affect the peripheral nervous system. Myopathies, diseases of peripheral nerve

and neuromuscular junction, amyotrophic lateral sclerosis (ALS), muscular dystrophy (MD), and

spinal muscular atrophies (SMA) are common types of these diseases and disorders and are

associated with premature death in nearly all patients affected. Neuromuscular diseases and

disorders tend to be progressive in nature, which results in abnormal muscle degeneration or

myasthenia and fatigue. Problems with neuromuscular disorders include difficulty with

swallowing and sometimes breathing, and physical weakness that worsen with activity. At

present, there is no cure for most of these diseases and disorders, and their treatments in general

have rather been disappointing as the efficacy of long-term therapy is yet to be established. In

quest of developing an effective treatment, scientists and researchers have recently turned their

interests to nicotinamide adenine dinucleotide (NAD), an important coenzyme in the eukaryotic

cells that participates in many crucial biochemical processes of cellular respiration and energy

production in order for animals to survive and thrive. Although NAD seems promising, higher

level of NAD does not have an adequate effect on slowing down the progress of human

neuromuscular diseases and disorders because there is not enough evidence to conclude that the

coenzyme helps decelerate the progress of myasthenia. Thus, treating the muscles alone for

neurological or nerve-related conditions and disorders is universally inefficient. Reliability is the

most important aspect of science, and false publication, such as announcing that NAD helps

down the progress of human neuromuscular diseases and disorders, will most certainly result in

serious consequences on society as a whole.

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 There is not enough evidence to conclude that NAD helps decelerate the progress of

myasthenia because studies and experiments results on the correlation between the levels of

NAD or its dependent precursors and the progress of myasthenia is highly controversial and

conflicting. Thus, the dynamic modulation of activation for any particular pathways, which

activate specific tissues or cell types that are capable of responding to the change in levels of

NAD and its precursors, are uncertain and require further research. Frederick et al. found that an

overexpression of the NAD-dependent deacetylase SIRT1, an NAD+ (reduced form of NAD)

forms dependent deacetylase, in the brain has recently been shown to improve muscle

physiology, whereas overexpression of the enzyme in the muscle itself was ineffective in

decelerate the progress of myasthenia (Frederick et al. 1557). Popular proposed modulation of

activation pathways of NAD and its dependent precursors includes nicotinamide riboside kinase

2b (Nrk2b)-mediated NAD+ biosynthesis to regulate muscle cell adhesion to laminin by Goody

et al., placing SIRT gene at the crossroad between energy homeostasis by Tokin et al., and

restoration of the NAD+ pool through nicotinamide riboside (NR) by Kubwabo et al. Although

in consensus on the potency of NAD+ in mitochondrial biogenesis, Michelle Goody, a current

prominent postdoctoral researcher on NAD and muscular dystrophy, and compatible researchers

remain nave in comprehending the mechanisms of these alternative salvage pathways and how

to overcome them.

NAD is inadequate as a treatment for human neuromuscular diseases and disorders since

NAD has been reported to only helps maintain fibers strength and regeneration from damage

muscle, yet neuromuscular diseases and disorders affect the nerves that control voluntary

muscles. Therefore, treating the muscles alone for neurological or nerve-related conditions and

disorders is universally inefficient. Motoneurons and their electrical stimulation languish and

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eventually die following the progression of neuromuscular diseases and disorders. Through

analysis of current research and Liu et al.s acknowledgement, it is confident to conclude that

although intact axons reinnervate nearby muscle fibers through muscle-specific transgenic

methods such as activating NAD and its dependent precursors helps compensate for the death of

motoneurons, when an entire motoneuron pool dies, there is complete denervation (Liu et al.

660). Assumed by hypothesis, these NAD-boosting strategies have the capability of enhancing

mitochondrial biogenesis and metabolic functions in muscle tissues, specifically of skeletal

muscles, which in turn helps maintain fiber strength and regeneration from damage. Yet, these

activation pathways are self-sufficient to muscle fibers alone and are independent from

motoneuronsthe fundamental cause of symptoms in neuromuscular diseases and disorders.

According to Romero et al., fatigue and physical degeneration symptoms in neuromuscular

disease and anesthesia often caused by autoantibodies directed to the nicotinic acetylcholine

receptor, decreasing the safety factor of neuromuscular transmission, rather than muscles

condition themselves (Romero et al. 455). This statements hypothetically comparable to patients

with paralysis, whose healthy muscles experience degeneration due to damaged nerves.

Furthermore, in Liu et al.s experimentation on reinnervated muscles in Fisher rats, electrical

stimulation of the proximal stump of a transected peripheral nerve increased the number of motor

axons that grew across the suture line and sped up the return of muscle function by increasing

BDNF expression in neurons (Liu et al. 668). Motoneurons stimulation intervention treatments

such as electrical stimulation on embryonic neurons transplanted into peripheral nerve in

neuromuscular diseases and disorders are more effective than maintaining muscle fibers strength

and regeneration from damage alone.

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 The general affirmation or assumption from the science society, where NAD helps down

the progress of human neuromuscular diseases and disorders, is unreliable since the majority of

experimentations on the coenzyme and its dependent precursors are done on nonhuman or

animal embryonic stem cells and myocytes, which generate biases from the affirmation on the

positive correlation of NAD and the progression of neuromuscular disorders. According to Dr.

Aysha Akhtar, a double Board-certified neurologist and preventive medicine/public health

specialist, the bottom line is that animal experiments, no matter the species used or the type of

disease research undertaken, are highly unreliableand they have too little predictive value to

justify the resultant risks of harms for humans (Akhtar, 413). Statistics show that animal-based

methods used in preclinical testing to select drugs for human use are not only unsafe, but also

expensive, time-consuming, and unreliable. SIRT1 has been reported to have positive

involvement in the protection against metabolic disorders, against cancers and in the

enhancement of life span in animal research. Yet, among skeptical scientists, when Ho et al.

stably introduced the SIRT1 gene into human vascular smooth muscle cells (SMCs), they found

that overexpressing SIRT1 alone in human vascular SMCs has minimal effect on replicative

longevity but that SIRT1 can strikingly extend lifespan if the aging-related decline in the NAD+

salvage pathway can be overcome (Ho et al. 3082). Species differences in anatomy, organ

structure, metabolic functions, and mechanisms of DNA often give inadequate or erroneous

information when attempt to apply chemical and drug absorption in animal data to human

diseases and drug responses.

Research has long reported that NAD deficiency in myocytes have association with

myasthenia in skeletal muscles wasting on voluntary body movements, and myasthenia is also

the core symptom in neuromuscular diseases and disorders. In correspondence with previous

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assertion, notable studies of those by M. Goody, Kubwabo, Tokin, etc., indicate that higher level

of NAD helps slow down the progress of myasthenia through improving the structures and

activities of skeletal muscles, therefore, should help slow down the aggressive progression of

these diseases and disorders. Although these affirmations have scientific stand, there are also

significance of experimental data results by researchers, such as from Ho, Frederick, etc.,

suggesting that an increasing expression of NAD and its dependent precursors has little to no

significant positive influence on muscle strength and regeneration from damage, nonetheless

have efficiency on the aid against aggressive progression of neuromuscular diseases and

disorders. Some NAD-dependent precursors even exhibit negative effect. Ho et al.s

experimentation on potential longevity in proliferating human vascular SMCs yielded a p-value

less than the significance level () of 0.05, suggesting that an increasing expression of SIRT1 in

aging human SMCs has little effect on SMC lifespan, despite an otherwise aging-related decline

in SIRT1 expression (Ho et al. 3084). Reduced potential longevity is a feature that is apparent to

patient with myasthenia gravis, a common neuromuscular disease. Similar in findings, Frederick

et al.s experimentation on tissue-autonomous effects on oxidative metabolism on Nampt+/WT

mice disagrees with previous affirmations, and reported that expression of the transcript for

nicotinamide N-methyltransferase, which competes with NAMPT to metabolize NAM, was low

in skeletal muscle and unaffected by genotype (Frederick et al. 1555). Homogeneous with many

research, both of these experimental data results dispute the affirmation on the positive

correlation between NAD and the progress of myasthenia in neuromuscular diseases and

disorders. Theoretically, higher level of NAD and its dependent precursors degenerate the

progress of myasthenia is an appealing hypothesis, its actual statistical data are controversial and

suggest otherwise.

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 As supported by many doctors and researchers, degenerating muscle, whether from

muscular dystrophy or neuromuscular diseases, loses its mitochondria (the energy supply) and

essential cofactor NAD-dependent precursors, such as NAD+, while gaining an extra load of

enzymes that use up the precursors (Ryu et al. 362). This evidence indicates that higher level of

NAD and helps improve muscles condition and slow down the progress of myasthenia in human

muscular dystrophy and neuromuscular diseases. Although the report indicates that there may

exist certain relationship between the level of NAD-dependent precursors and neuromuscular

diseases and disorders, it is not confident enough to claim that there is a positive correlation

between NAD and the progress of myasthenia, and that the coenzyme helps slow down the

progress of neuromuscular diseases as previously addressed. Furthermore, NAD-dependent

precursors is an umbrella for many related but distinguished cofactors and cannot be generalized

into a single type of coenzymeNAD. The deprivation of mitochondria also stated to be a

crucial participant in myasthenia, and should not be neglected in evaluation. Thus, the dynamic

modulation of activation for any particular pathways, and specific tissues or cell types that are

capable of responding to the change in levels of NAD and its precursors, are uncertain and

require further research.

Although science is tentative, it provides facts and scientific methods to design and

implement research, and therefore it is essential for a proposed notion to have confidence, where

observations and results must be repeatable, testable and confirmable by other scientists and

researchers. Through controversial research and studies proclamations and inconsistent

experimental data reports, it is uncertain whether higher level of NAD has adequate effect in

decelerating the progress of myasthenia, much less if the coenzyme helps slow down the

progress of human neuromuscular diseases and disorders. The combination of current findings

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suggests that modification of nerve stimulation, accompanied by additional layers of NAD and

its dependent precursors regulations, presumably have adequate effect on improving physical

activities in different contexts. A deeper understanding of the muscle tissues and nerve impulse

mediate specific processes and effects will greatly facilitate the development of therapeutics to

combat comorbidities neuromuscular diseases and disorders. Motoneurons stimulation

intervention and muscle-specific transgenic approach contribute progressive breakthroughs and

understandings toward dissecting the mechanisms of these diseases and disorders for more

effective treatments.

Works Cited

Akhtar, Aysha. The Flaws and Human Harms of Animal Experimentation. Cambridge

Quarterly of Healthcare Ethics, vol. 24, no. 4, Oct. 2015, pp. 407-419. Cambridge University

Press, doi: 10.1017/S0963180115000079. Web. 4 Dec. 2016.

Frederick, David W, et al. Increasing NAD Synthesis in Muscle via Nicotinamide

Phosphoribosyltransferase is Not Sufficient to Promote Oxidative Metabolism. The Journal

of Biological Chemistry, vol. 290, no. 3, Jan. 2015, pp.1546-58. MEDLINE,

doi:10.1074/jbc.M114.579565. Web. 25 Sep. 2016.

Ho, Cynthia, et al. SIRT1 Markedly Extends Replicative Lifespan if the NAD + Salvage

Pathway is Enhanced. FEBS Letters, vol. 583, no. 18, 2009, pp. 3081-5. John Wiley & Sons,

Inc., doi:10.1016/j.febslet.2009.08.031. Web. 29 Sep. 2016.

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Liu, Yang, et al. Effects of Brief Electrical Stimulation on Embryonic Neurons Transplanted

into Peripheral Nerve. J Neurophysiol, vol. 112, no. 3, Aug. 2014, pp. 660-670. ProQuest

Dissertations Publishing, doi:10.1152/jn.00806.201. Web. 5 Nov. 2016.

Romero, Alan, et al. Neuromuscular disease and anesthesia. AANEM Monograph: Muscle &

Nerve, vol. 19, no. 1, Sep. 2016, pp. 451-460. Wiley Periodicals, Inc.,

doi:10.1002/mus.23817. Web. 5 Nov. 2016.

Ryu, Dongryeo, et al. NAD+ repletion improves muscle function in muscular dystrophy and

counters global PARylation. Science Translational Medicine, vol. 8, no. 361, Oct. 2016, pp.

361-390. American Association for the Advancement of Science,

doi:10.1126/scitranslmed.aaf5504. Web. 27 Oct. 2016.