During space flight or any form of traumatic injury which involves muscle wasting such as cancer, AIDS, burns, and hospital immobilization, all kinds of catabolic and muscle atrophy pathways are turned on (2).The ubiquitin-proteasome pathway (UPP) is the predominant catabolic pathway for this muscle tissue breakdown. Myostatin turns on the UPP pathway and breaks down muscle tissue (37). Unfortunately, the UPP pathway also becomes activated during periods of high intensity exercise, stress when cortisol is being secreted, and calorie restriction25. UPP is a major enemy for anyone trying to get ripped up without losing muscle.
It’s no coincidence that marathon runners are mostly skin and bones. Marathon runners’ and other endurance athletes have an increase in UPP from not eating enough and excess training which causes excess muscle breakdown. In a recent study in the Journal of Applied Physiology, UPP responses were analyzed in 6 experienced resistance trained men and compared to marathon runners. Subjects had muscle biopsies before, immediately after, and 24 hours post-exercise. The running protocol induced a greater number of genes associated with muscle catabolism compared with the resistance exercise bout. In general, the mRNA expression of the UPP is suggestive of a greater induction of muscle breakdown following endurance exercise. The study concluded that following endurance exercise, the induction of muscle breakdown genes was greater than following resistance exercise. The study provides insight to the muscle adaptive response at the molecular level that leads to a decreased muscle fiber size with endurance training47. Most people when dieting make the mistake of losing too much muscle mass when trying to get ripped up, but fear not this article will give you the inside edge to turning off the catabolic switch.
Triggers of UPP: Excess Thyroid, Cortisol, Low Insulin, Calorie Restriction
Everyone knows that cortisol is a catabolic hormone. Cortisol breaks down muscle tissue and can be overactive during periods of elevated stress (e.g. over-training, diet, emotional stress). Cortisol causes muscle tissue breakdown through the activation of UPP (23). Researchers have discovered a few other mechanisms which trigger the UPP pathway. Thyroid has potent fat loss properties, as elevated thyroid results in increased calories burned, particularly in the form of heat. People with excess thyroid production are often in a catabolic state as excess thyroid hormone can cause muscle protein breakdown mainly mediated by increasing UPP activity (21). Additionally, low level of plasma insulin triggers protein breakdown in muscle through activation of the UPP (6, 7). As you know, insulin is an anti-catabolic hormone and suppresses protein breakdown. It’s interesting that diabetics’ or patients with insulin resistance have increased muscle protein breakdown and increased muscle atrophy due to defects in insulin signaling. The increased breakdown of muscle in diabetics is also due to elevated UPP levels (42). Low carb diets are highly effective for losing fat by controlling insulin. Some diet gurus recommendperiodic high-glycemic meals which spike insulin especially post-workout; this is not only effective for maintaining an anabolic state, but the insulin spike which results also shuts down the UPP pathway. A new study published in BMC Molecular Biology also reports that increasing amino acids or leucine alone acts with insulin to down regulate muscle protein breakdown and reduce UPP8. The use of l-leucine while dieting therefore seems to be effective for reducing muscle tissue breakdown by reducing UPP. In addition to hormonal stimulators of UPP, resistance exercise also increases UPP which is a normal adaptation to exercise.
Resistance Exercise and Ubiquitin-Proteasome Pathway (UPP)
Strenuous resistance exercise stimulates adaptation in skeletal muscle. UPP is part of the normal adaptations to exercise, but overtraining can significantly increase UPP and stop muscle gains. Muscle has a memory system that further protects it from exercise-induced damage. An increase in UPP has been found to occur after intense resistance exercise (26). This increase in UPP mediates a rise in protein breakdown followed by an immediate increase in protein synthesis that is required for muscle adaptation from exercise to occur. It has been reported that an increase in UPP is associated with post-exercise increases in damaged muscle fibers (27). Eccentric exercise also increases UPP the most compared to other exercises. Thompson and Scordalis (28) evaluated muscle biopsies obtained from the biceps 2 days after a bout of damaging maximal eccentric exercise. They found a 55% increase in UPP after exercise, relative to non-exercised control muscle; however after repeated eccentric exercise bouts there seems to be a muscle adaptation that takes place protecting muscle from further damage and subsequent increases in UPP activity. Willoughby and colleagues (29) measured muscle UPP after eccentric knee extension exercise performed by healthy volunteers on two successive trials. They observed an increase in UPP was larger after the first trial than the second. This means muscle tries to “protect” itself from further muscular damage. Eccentric exercise produces the most robust changes whereas concentric exercise tasks stimulate UPP but appear to have a lesser impact. Acute increases in UPP are part of the normal adaptation to resistance exercise but chronically elevated levels caused by diet and stress (physical and emotional) lead to excess muscle tissue breakdown.
The Burn Victim Anti-Catabolic Diet
While trying to get ripped, the reduced amount of calories one consumes combined with cardio and resistance exercise can lead to an increase in cortisol that can lead to a catabolic condition. Did you know that there is an anti-catabolic diet that was specially formulated for burn victims to reverse muscle catabolism? The Shriners’ burn diet consists of high protein and fats high in anti-inflammatory omega-3 fatty acids while low in pro-inflammatory omega-6 fatty acids. The diet also has been shown to enhance muscle recuperation from burns compared to the standard hospital diet (19). When reducing calories and increasing cardio to lose fat, the use of agents that reduce muscle catabolism are beneficial. It should be of no surprise that testosterone administration has been shown to decrease UPP (23). The use of clenbuterol is known to exert its anabolic effects largely through reduced protein muscle breakdown. Clenbuterol has been shown to significantly reduce UPP; it also appears that clenbuterol preferentially inhibits the UPP in the fast-twitch muscles (30). Reducing muscle catabolism is essential in the medical field as trauma doctors know that reversing the catabolic state in trauma victims is a matter of life and death. In severe injury, such as burns, skeletal muscle breakdown far exceeds synthesis, even during feeding1. The traumatic insult is also associated with increased cortisol secretion. The increase in blood cortisol concentrations correlates with the severity of the injury and often persists for weeks after injury (2, 3). Although trauma is accompanied by increased circulating concentrations of glucagons and catecholamines, the loss of muscle mass is likely due primarily to the effects of cortisol4. The effects of cortisol on skeletal muscle are to increase protein breakdown which increases UPP production5. Did you know that there is a specially formulated medical drink to reverse catabolic conditions called JUVEN? Juven is a therapeutic nutrition drink clinically shown to help build muscle in cancer and HIV/AIDS and to stop muscle wasting. The best part about it is that you can get all the ingredients at a local health food store. Juven contains a patented blend of three key ingredients- HMB (beta-hydroxy-beta-methylbutyrate), arginine, and glutamine. The exact dosing in all the research studies to enhance prevent muscle loss is 1.2 g of HMB, 7 g of L-glutamine, and 7 g of L-arginine taken 2X daily. Most of the studies to date have administered this blend twice a day. Some of the studies are showing increases in lean muscle mass with this supplementation without the use of resistance exercise (40, 41). It is important to note that all 3 components work through different metabolic pathways and have synergistic effects. Glutamine- Muscle cell concentrations of glutamine are far higher than blood levels. Plasma and intramuscular glutamine concentrations drop during metabolic stress such as surgery, burns, or trauma (9). Glutamine also increases heat-shock proteins which increase muscle hypertrophy (10, 11). Heat-shock proteins are ‘cellular chaperones’ involved in the management of stress-induced protein cell destruction. Glutamine depletion results in diminished synthesis of heat-shock proteins. Recently, glutamine has been shown to increase heat-shock protein approximately fourfold in critical illness (12). Glutamine can also increase tissue glutathione levels and enhance antioxidant capacity. The use of glutamine seems to be especially warranted during dieting when caloric restriction, exercise frequency, and exercise intensity are at their highest. Arginine- Dietary supplementation with arginine has also been shown to safely induce positive nitrogen balance in humans possibly by increasing muscle protein synthesis and inhibiting muscle proteasome (enzymes that breakdown muscle) activity (38). The most important pathway of arginine metabolism appears to be its conversion to orthinine in the liver, which is a precursor for protein synthesis. Arginine supplementation, usually up to 20 g/d, has been reported to reduce weight loss and nitrogen loss and improve nitrogen retention and wound healing. The mechanism for this action is unclear. One mechanism may be stimulation of the release of GH release. Another mechanism may be thru stimulation of nitric oxide production. As NO is directly involved in many physiological mechanisms relevant to hormone release, and muscle regeneration. For example, the enhanced muscle regeneration effects of L-arginine appears to be dependent on the NO pathway, as supplemental dietary arginine enhances muscle regeneration in normal but not those deficient in NO (25). Beta-hydroxy beta-methylbutyrate (HMB) – is a metabolite of the branched-chain amino acid leucine. HMB is metabolite of the amino acid leucine, leucine alone can stimulate protein synthesis, inhibit protein breakdown, and reduce activation of UPP (46). You probably remember HMB a few years ago but it kind of just faded away, however its importance should not be underestimated. It seems that HMB may be making a comeback. In the Journal of Trauma, the use of HMB was found to significantly improve nitrogen retention in patients that were seriously injured (40); this effect may be mediated by the actions of increasing leucine metabolism. Also HMB has been shown to reduce muscle tissue breakdown by inhibiting UPP43. One study looked at the validity of several supplements (creatine, HMB, chromium, DHEA, androstenedione, and protein.) for increasing lean muscle mass. The two supplements, creatine and HMB, were the only supplements have data supporting their use to augment lean mass and strength gains with resistance training (39).
Other Potent Anti-Catabolic Agents
Fish Oils- More Than Just Cardiovascular Protection- Omega-3 fatty acids found in fish oils contain potent anti-inflammatory and anti-catabolic ingredients. In fish oils, there are two active ingredients: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA seems to be a more important mediator of reducing muscle tissue breakdown than DHA. EPA reduces muscle tissue breakdown as it down-regulates the expression of the genes that control key regulatory components of the major pathway that leads to contractile protein break down in muscle. EPA effectively blocks or ‘deactivates’ UPP (44). Both EPA and DHA, found in fish oils are crucial for increasing insulin sensitivity (24). Both EPA and DHA form vital components within cell membranes that allow insulin to transport nutrients into cells. Increasing insulin sensitivity may also increase serum testosterone levels. A recent study showed that testosterone levels are directly related to insulin sensitivity (13). Another benefit to using fish oils is that fish oils lower serum triglycerides and improve cardiovascular health (14). High testosterone levels have been found associated with low triglyceride levels15 and a decrease in testosterone levels are associated with an increase in serum triglycerides (18). Thus, higher endogenous testosterone levels in men are associated with a more favorable lipid profile. Most but not all population studies have reported a positive association between testosterone levels and HDL cholesterol (good cholesterol) in adult men (15-17). Curcumin Enhances Muscle Regeneration- Curcumin, the active ingredient in the spice turmeric is a non-toxic, anti-inflammatory, antioxidant, and an anti-estrogen (45). Curcumin is such a potent anti-oxidant that when researchers blasted the leg muscles of mice with radiation, curcumin significantly reduced the radiation induced inflammatory damage in muscle (34). Curcumin inhibits a major pathway of muscle tissue breakdown called the NF-kB pathway. Don’t get bothered by the name just remember that activation of NF-kB in skeletal muscle increases UPP expression in muscle, consistent with a role for NF-kB plays a role in muscle protein catabolism31. In addition, recent studies have suggested a possible role for NF-kB in the development of insulin resistance (32). Okay, enough of the tree hugging anti-oxidant stuff…you want the hardcore muscle info! It has been demonstrated that treatment with curcumin after local muscle injury leads to faster restoration of normal tissue as well as to increased expression of biochemical markers associated with muscle regeneration33. Additionally, curcumin blocks muscle protein loss suggesting it has potential usefulness in the treatment of muscle wasting and possibly, other inflammatory conditions (35). Curcumin: A Safe Alternative to NSAIDS- With hardcore training, all bodybuilders are susceptible to the occasional sore knee or elbow, or strained muscle. NSAIDS are good for pain relief, but current research suggests that curcumin may inhibit muscle hypertrophy. Curcumin may be a safer and non-toxic alternative. Evidence suggests that in some experimental conditions curcumin can have similar anti-inflammatory activity as some of the common non-steroidal anti-inflammatory drugs (NSAIDs) like Indomethacin, Vioxx, Celebrex, and Ibuprofen, but without many of the side effects such as gastrointestinal distress and cardiovascular complications. Recently, it was shown that curcumin caused a decrease in whole body markers of inflammation and can speed recovery following exercise-induced muscle damage (36). The performance effects are reflected by a reduction in plasma creatine kinase and inflammatory cytokine concentrations which are typically associated with muscle damage and inflammation. As opposed to the NSAID drugs which specifically target COX- 2 inhibition curcumin’s effects appear to be more specifically targeted at NF-kB, and therefore their anti-inflammatory effects may come with less potential for serious side-effects. Remember, preventing or minimizing muscle breakdown during intense resistance training is incredibly important; it’s half the battle won in terms of speeding recovery and gaining muscle mass. Key Points:
- The ubiquitin-proteasome pathway (UPP) is the predominant catabolic pathway for muscle tissue breakdown.
- UPP is increased by excess thyroid, cortisol, low insulin, diet, excess cardiovascular training, and intense resistance exercise.
- Inhibitors of UPP are insulin, HMB, arginine, leucine, glutamine, curcumin, and fish oils.
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