*Lawrence M. Schwartz and **Robert Gorter, MD, PhD and ***Guru Brar
*Department of Biology, Morrill Science Center, University of Massachusetts, Amherst, MA, USA
**Emeritus Professor, University of California San Francisco Medical School (UCSF), USA
***Professional trainer of movie stars, top athletes and body builders, India
January 25th, 2019
New research shows that extra nuclei gained during exercise persist even after a muscle shrinks from disuse, disease or aging — and can be mobilized rapidly to facilitate bigger gains on retraining
Newswise — The old adage “use it or lose it” tells us: if you stop using your muscles, they’ll shrink. Until recently, scientists thought this meant that nuclei – the cell control centers that build and maintain muscle fibers – are also lost to sloth.
But according to a review published in Frontiers in Physiology, modern lab techniques now allow us to see that nuclei gained during training persist even when muscle cells shrink due to disuse or start to break down. These residual ‘myonuclei’ allow more and faster growth when muscles are retrained – suggesting that we can “bank” muscle growth potential in our teens to prevent frailty in old age. It also suggests that athletes who cheat and grow their muscles with steroids may go undetected.
Our biggest cells are in our muscles, and they’re all fused together
Syncytium. Sounds like a neo-noir comic book series. It’s actually a special type of tissue in your body, where cells are fused together extra close – so close, that they behave a like a giant single cell.
“Heart, bone and even placenta are built on these networks of cells,” says Lawrence Schwartz, Professor of Biology at the University of Massachusetts. “But by far our biggest cells – and biggest syncytia – are our muscles.” Like the Sin City series, it appeared at first that everything was black and white with syncytia.
“Muscle growth is accompanied by the addition of new nuclei from stem cells to help meet the enhanced synthetic demands of larger muscle cells,” explains Schwartz. “This led to the assumption that a given nucleus controls a defined volume of cytoplasm – so that when a muscle shrinks or ‘atrophies’ due to disuse or disease, the number of myonuclei decreases.”
“A muscle can gain nuclei, but never loses them”
This assumption long seemed valid, with many researchers reporting the presence of disintegrating nuclei in muscle tissue during atrophy induced by inactivity, injury or paralysis. But modern cell-type-specific dyes and genetic markers have shown that the dying nuclei other researchers had detected were in fact inflammatory and other cells recruited to atrophic muscle.
The new evidence paints a very different picture of muscle syncytium.
“Two independent studies – one in rodents and the other in insects – have demonstrated that nuclei are not lost from atrophying muscle fibers, and even remain after muscle death has been initiated.”
This strongly suggests that once a nucleus has been acquired by a muscle fiber, it belongs to the muscle syncytium – probably for life. But Schwartz, for one, is unsurprised by the new findings.
“Muscles get damaged during extreme exercise, and often have to weather changes in food availability and other environmental factors that lead to atrophy. They wouldn’t last very long giving up their nuclei in response to every one of these insults.”
“Use it or lose it – until you use it again”
Since myonuclei are the synthetic engine of muscle fibers, retaining them should enable muscle size and strength to recover more quickly after one of these insults, and help to explain the phenomenon of ‘muscle memory’.
“It is well documented in the field of exercise physiology that it is far easier to reacquire a certain level of muscle fitness through exercise than it was to achieve it the first place, even if there has been a long intervening period of detraining. In other word, the phrase “use it or lose it” is might be more accurately articulated as ‘use it or lose it, until you work at it again’.”
As such, the findings have important implications beyond understanding muscle biology.
“Informing public health policy, the discovery that myonuclei are retained indefinitely emphasizes the importance of exercise in early life. During adolescence muscle growth is enhanced by hormones, nutrition and a robust pool of stem cells, making it an ideal period for individuals to “bank” myonuclei that could be drawn upon to remain active in old age.”
The findings also support frequent drugs testing for competitive athletes, with permanent bans for proven steroid cheats since they will benefit from the steroids long after their use has ended.
“Anabolic steroids produce a permanent increase in users’ capacity for muscle development. In keeping with this, studies show that mice given testosterone acquire new myonuclei that persist long after the steroid use ends.”
Cannabidiol (CBD) is quickly becoming a vital part of many workout routines. CBD is an important part of any holistic health and wellness routine. Whether one is a professional athlete, amateur jogger or busy parent, this beneficial supplement made from hemp can help. Whatever style of fitness regimen you prefer, muscle development and muscle recovery play key roles in overall health and wellbeing: also at older age.
Since the World Anti-Doping Agency lifted its ban on CBD, many fitness professionals and athletes use CBD as the staple for their high-performance fitness regimens to build muscle and boost stamina. CBD can do a lot of ‘good’ for the human body. That being said, it is important to use the highest quality CBD from natural hemp oil, from a CBD supplier one can trust.
From recent research on the Endocannabinoid System, it has been documented beyond doubt that CBD engages CB2 receptors in the limbic and paralimbic regions of the brain, the control centers of the Endocannabinoid System responsible for regulating sleep and mood. Nearly 25 percent of Americans struggle to achieve deep REM sleep. However, with the support of CBD, regular deep REM sleep can be achieved to augment protein synthesis for building muscle tissue at the most optimum time when growth inhibiting cortisol levels are at a minimum. This is one indirect way CBD helps to manage cortisol levels.
A study published in September 2018 by the Brazilian Journal of Medical and Biological Research documents CBD works directly with the Endocannabinoid System to interfere with cortisol secretion as reported by the US National Library of Medicine and National Institutes of Health, where subjects experienced a significant decrease in cortisol levels in their blood. This means that CBD can slow the breakdown of muscle mass and help athletes to build more muscle.
We know about CBD’s calming anti-anxiety and mood-regulating effects when working in natural harmony with our Endocannabinoid Systems. It is easy to see how CBD’s multiple and very beneficial therapeutic effects, and its direct anti-catabolic action all combine to keep cortisol at the properly balanced levels to benefit our systems.
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1) These observations have a number of implications for both understanding the basic biology of muscle and for developing potential therapeutic interventions. While there is substantial data reporting the presence of apoptotic nuclei within the tissue following atrophic insults, recent data suggests that these are not true myonuclei, but rather, condemned mononuclear cells that reside outside the muscle fiber. The primary reason for this discrepancy is that the traditional tools used for detecting apoptosis lack the resolution required to adequately determine which side of the sarcolemma a dying cell resides. Methods that label myonuclei specifically, either via in vivo injections of fluorescent dyes (Bruusgaard and Gundersen, 2008) or via genetic manipulations to express marker proteins (Duddy et al., 2011), reveal few if any apoptotic nuclei within the labeled fibers. The recent demonstration that antibodies directed against Protein Pericentriolar Material 1 (PCM1) label only authentic myonuclei offers a promising tool that can be applied to the traditional histological materials that are routinely analyzed in the field (Winje et al., 2018b).
2) The failure of skeletal muscles to employ apoptosis as a mechanism for eliminating myonuclei is not surprising. It appears that mature skeletal muscle is largely precluded from initiating apoptosis in that it upregulates the expression of potent survival proteins like X-linked inhibitor of apoptosis protein (XIAP) (Smith et al., 2009) and apoptosis repressor with caspase recruitment domain (ARC) (Xiao et al., 2011), while simultaneously expressing low levels of apoptosis mediators like apoptotic protease activating factor 1 (Apaf-1) (Burgess et al., 1999). This makes sense teleologically since muscles are subject to extreme perturbations, including disruption of the sarcolemma following intense exercise, so it would be catastrophic if they triggered cell death rather than initiated tissue repair and possibly hypertrophy. Like other terminally differentiated cells, muscles tend to employ non-apoptotic mechanisms, most notably autophagic PCD (also known as Type II degeneration) (Clarke, 1990; Schwartz et al., 1993; Kole et al., 2013; Ginet et al., 2014) when they die during development.
3) Even if there was a mechanism by which muscles could selectively target individual nuclei, it is not clear that this would be beneficial. In fact, the retention of “surplus” nuclei during atrophy confers a distinct advantage for the individual since skeletal muscles frequently undergo cycles of atrophy and hypertrophy in response to environmental conditions such as food availability and physical activities. The ability to recover quickly by utilizing pre-existing myonuclei may serve an important role in adaptation (Jackson et al., 2012) and help explain the phenomenon of “muscle memory” (Staron et al., 1991; Gundersen, 2016). It is well documented in the field of exercise physiology that it is far easier to reacquire a certain level of muscle fitness through exercise than it was to achieve it the first place, even if there has been a long intervening period of detraining. In other word, the phrase “use it or lose it” is might be more accurately articulated as “use it or lose it, until you work at it again.” This has been demonstrated directly by another experiment from the Gundersen lab that demonstrated that once a muscle has acquired new nuclei, it retains them long after the hypertrophic stimulus is removed. They induced muscle hypertrophy in female mice by treating them for 2 weeks with testosterone and then examined the muscles 3 weeks after steroid withdrawal (Egner et al., 2013). Muscle volume had returned to baseline but the newly acquired nuclei persisted even 3 months later. When the muscles were subjected to overloading to reinitiate hypertrophy, the steroid-treated ones rapidly underwent a 36% increase in fiber volume while control muscles only grew by 6%. These data suggest that the “surplus” nuclei could be mobilized rapidly to facilitate retraining.
4) These observations have potential implications for public health policy. It has been shown that muscle growth, physiological function, and regenerative capacity all decline with age, largely due to reduced satellite cell proliferation (Blau et al., 2015). Consequently, exercise during adolescence, when muscle growth is enhanced by hormones, nutrition and a robust satellite pool, might functionally serve to allow individuals to “bank” myonuclei that could be drawn upon later in life to slow the effects of aging and possibly forestall sarcopenia.
5) In addition, these data have implications in the area of competitive sports. The use of anabolic steroids is a potent stimulus for muscle hypertrophy and the addition of new myonuclei (Egner et al., 2013). Since these nuclei persist long after the steroid use ends, athletes likely derive the benefits of illegal drug use without the risk of detection.
6) In summary, while the addition of new nuclei with muscle growth is largely accepted, the apoptotic loss of nuclei with atrophy cannot be supported, suggesting that strict interpretation of the myonuclear domain hypothesis cannot be supported. Instead, it appears that once acquired, myonuclei persist even when a muscle becomes atrophic or initiates cell death.
7) For professional athletes who depend on muscle mass and strength later in life, it documents that as a teenager, one should build as much muscle as possible: in mass and in strength. In case of less training or inactivity caused by aging, illness, the high number of myonuclei stay available and rebuild muscles faster; back to their original state. This has consequences for sincere coaches and their clients alike.
8) Cannabidiol (CBD) plays an important role to enhance in a completely natural way the increase of myonuclei and prevent any damage to muscle and tendon which leads to degenerative and aging processes by inhibiting the COX-2 pathway and regulates cortisol levels (“stress hormones”) during and after work-out.
Aging, Cell Biology, Body Weight, Musculature, Sports Medicine
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