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Butyrate Way back when we talked about SCFAs positive effects on inflammation and permeability of the gut, we said we would get back to its actions outside of the gut, and here we are. In addition to butyrate’s peripheral anti-inflammatory effects via keeping LPS contained inside the gut, it also directly inhibits TNF-alpha and the inflammatory response to LPS (460, 461). Elimination of the gut microbiome (thus SCFA production) with antibiotics decreases IGF-1, which is restored with SCFA administration (462). Dietary administration of fellow SCFA, propionate, up-regulated the expression of GH, IGF1 and down-regulated myostatin (463). Butyrate improves insulin-resistance in skeletal muscle, along with its induction of Akt (464, 465). And, it increased muscle fiber cross-sectional area along with improving glucose metabolism in aged subjects (466). Let’s take a closer look at some of the several mechanisms through which it works. GLP-1 Activation of Free Fatty Acid Receptors (FFAR2 & FFAR3) in the gut by butyrate stimulates the release glucagon-like peptide-1 (GLP-1) which then enters the blood stream (467, 468). Much like insulin, GLP-1 activates the anabolic Akt/mTOR pathway (469, 470, 471, 472). It also promotes dilation of muscle microvascular (473, 474). This enhances nutrient uptake in the muscle cell and is dependent on Akt/mTOR upregulation of nitric oxide production (475, 476). Its effects in this regard were both independent of, and additive to, insulin (477, 478). Recall also the positive effects of NO on satellite cell activation, muscle regeneration, and repair discussed earlier. In addition to skeletal muscle microvasculature, GLP-1 also significantly increases vasodilation and blood flow in large vessels like the brachial and radial arteries and femoral vein (479, 480). Treatment with GLP-1 improves exercise capacity and mitochondrial function, as well as skeletal muscle mass and strength (481, 482). HDAC While GLP-1’s positive effects in muscle begin with butyrate activity in the gut, butyrate, itself, is also taken up from the gut and enters the systemic circulation producing direct actions that support muscle growth. One of the primary mechanisms is its function as a Histone De-Acetylase (HDAC) inhibitor. This is epigenetic stuff. To put it simply, epigenetics involves (heritable) changes in gene expression without change to the DNA sequence, itself. It basically changes how the DNA is interpreted, similar to translating a foreign language book. The original book (DNA) stays the same, but a different author (epigenetics) is going to translate it differently. Negative epigenetic changes are a huge part of the build-up of dysfunction with aging in everything from metabolism, to muscle mass, to the brain, with inflammation being a particular culprit (483, 484, 485). Propionate and acetate also augment histone acetylation, but the bulk of the data is on butyrate (486, 487). HDAC inhibition amplifies Akt/mTOR signaling, as well as preventing induction of atrophy genes (488). Increased histone acetylation blocks downstream activity of glucocorticoids, including FoxO (489, 490). Inhibition of HDAC during muscle disuse significantly attenuated both disuse muscle fiber atrophy and contractile dysfunction via FoxO (491). The effects of acetylation on FoxO, and other targets such as mTOR, appear to be quite similar to phosphorylation with Akt, though data is still new and scarce (492, 493). But, that will definitely be something to keep an eye on. Finally, inhibition of HDAC activity significantly enhanced androgen receptor mediated protein synthesis (494). You have likely heard the term “muscle memory”, but you may not know that skeletal muscle stem cells do indeed have a memory that is created epigenetically. Stem cells from muscles of young, aged, physically active, and diabetic subjects carry on their altered metabolic characteristics when isolated and cultured (495). In other words, the bad (or good) epigenetic build-up semi-permanently alters them to such an extent that it is maintained when they are taken out of subjects and grown in a lab. HDAC inhibitors promote muscle regeneration through epigenetic regulation of both satellite stem cells and differentiated muscle cells (496). Via upregulation of follistatin (basically the anti-myostatin), HDAC inhibition also blocks the adipogenic potential of stem cells, pushing them toward the formation of muscle cells rather than adipocytes (497, 498). The importance of HDAC inhibition reversing long-term damage from inflammation and aging basically cannot be understated. Heat Shock Proteins Butyrate also induces Heat Shock Proteins (499, 500). Heat Shock Proteins (HSPs) are called such because they were initially discovered in cells subjected to hyperthermia, but they function as a protective and subsequent regenerative and repair mechanism against all kinds of cellular stressors (501). Other HDAC inhibitors induce HSPs as well, suggesting this as butyrate’s mechanism in this regard (502, 503). Induction of HSPs protects intestinal epithelial tight junction barriers, decreasing LPS leakage, and reducing the inflammatory response (504). Increased HSP levels also reduce TLR-4, and the subsequent production of TNF-alpha and NF-κB (505). HSPs strongly blunt increases of cortisol to stressors (506, 507). The synthetic glucocorticoid dexamethasone decreased myotube diameter and protein content, and heat stress prevented this along with recovering Akt signaling (508). HSPs directly bind to and protect Akt, and HSP induction defends against glucocorticoid induction of catabolic FoxO via Akt (509, 510). Silencing of HSP genes decreases Akt and myotube diameter while increasing FoxO, and treatment with an HSP inducer reverses this (511). Exercise also increases HSPs, along with Akt and downstream anabolic signaling (512). Aged subjects have a blunted HSP response to exercise, along with decreased muscle repair, which is reversed with HSP overexpression (513). HSPs’ positive effects on muscle repair and regeneration seems to be to some extent from protection of satellite cells (514). Androgens and Clenbuterol also strongly upregulate HSP expression, with this likely being particularly important for Clen’s anabolic effects (515, 516, 517, 518). Angiotensin II Last but not least, butyrate protects against the negative effects of Angiotensin II (Ang II). Like butyrate, itself, Ang II produces effects both inside and outside the gut. But, its effects are negative. It is kind of a wingman of LPS in that regard. It also displays bi-directional communication between the gut and brain in hypertension, much like cortisol with stress (519). In addition to its effects on blood pressure, it is strongly induced by LPS and mediates some of the inflammatory response to it (520, 521, 522). LPS induction of Ang II may be through TNF-alpha, but it is also a direct ligand for TLR-4, just as LPS is (533, 534, 535). It is a really interesting molecule, and Renin-Angiotensin a really interesting system, as it ties high blood pressure in with inflammation, insulin resistance, and the cardiovascular system in Metabolic Syndrome. You will likely hear a lot more about it over the next 5-10 years, but parts of the understanding are still relatively in their infancy, so we are going to keep it fairly brief. There is a decrease in microbial richness and diversity in hypertension and with Ang II infusion, as well as decreases in acetate and butyrate producing bacteria (536). This is accompanied by increased intestinal permeability and decreased tight junction proteins (537). Butyrate administration elevated Akkermansia levels, with significant positive effects on inflammation and ROS, and led to improvement of hypertension (538). Butyrate significant reduces blood pressure, as well as TNF-alpha, in response to Ang II infusion (539, 540). Data on other HDAC inhibitors indicate that this may be a primary mechanism for butyrate’s antagonism of Ang II’s actions. HDAC inhibitors prevented inflammation and ROS from Angiotensin II (541). They also protected against Ang II induced hypertension and vasoconstriction (542). And, again, the semi-permanent nature of epigenetics makes this especially important. Outside of the gut, Ang II basically does all of the same bad stuff as LPS because, as we mentioned, it mediates some of LPS signaling, plus shares signaling downstream from TLR-4. It shares the same link between inflammation and insulin resistance, and ACE inhibitors or Ang II receptor blockade reverses these (543, 544, 545). It reduces protein synthesis and increases catabolism, leading to muscle atrophy (546). Ang II inhibits the insulin and IGF-1 signaling pathways via Akt inhibition (547, 548). It impairs insulin stimulated nitric oxide and vasodilation (549). This is, once again, via the Akt/mTOR pathway (550, 551). As a result, Ang II also reduces muscle regeneration and satellite cell differentiation into muscle fibers (552). Finally, it increases the glucorticoid/myostatin catabolic pathways (553, 554). Will it work for me and what to expect With the science out of the way, the obvious question is “How much do you need and/or should you want pro- and prebiotics to fix your gut and your body?” Because the gut and systemic inflammation affect every system, and basically every cell, in your body, a good probiotic/prebiotic combo kind of stands apart from any other category of supplement. It is most analogous to going from a shitty diet to a good diet or from an okay diet to a perfect one. We briefly mentioned hardgainers and the “skinny fat” phenotype, earlier. You definitely want to fix your gut. I would expect around an extra 10 lbs of muscle in a year, as your body starts living up to its genetic potential. For significantly fat people (and, even moreso, if showing signs of glucose intolerance), you absolutely need to fix your gut. I would expect very noticeable body composition changes in 1-3 months, and borderline miraculous ones in a year. This article has been about muscle mass, but as we alluded to with the mention of Metabolic Syndrome, the gut and inflammation play a huge role in health, as well. Other general parameters pointing toward its usefulness for you are being over 30, the fatter you are, the worse your diet is, being in a calorie surplus, and having a (personal or family) history of inflammatory related conditions (heart disease, blood pressure, auto-immune, IBS/IBD, etc.). On other hand, if you are 19, quite lean, on great diet with low-moderate carbs including fruits and veggies, with an iron stomach, and in a calorie deficit, it is not going to noticeably do a lot for you. It would be much more of a preventative measure to keep your cells young as you get older, to keep you still being awesome 5-10+ years from now. A big exception would be during bulking phases – and, the dirtier the bulk, the more it would help. Likewise, if you tend to go off the rails during holidays or vacations, it is damage control.
Outside of the Gut If you are not already convinced of the benefits of pro- and prebiotics on muscle mass, it gets even more interesting outside of the gut. Getting back to Lipopolysaccharide (LPS) produced by a dysfunctional microbiota, once it has escaped the leaky gut, it sets off an anti-anabolic, pro-catabolic cascade of inflammation and reactive oxygen species (ROS), systemically (298). As we have mentioned, your body views LPS as an outside, pathogenic invasion via TLR-4. And, it literally is, as these bacteria are living, foreign invaders, thus immune defenses are activated. In such an attack, metabolically expensive skeletal muscle is not prioritized – quite the opposite, in fact. Amino acids and protein synthesis are prioritized for the immune response, at the expense of muscle tissue (299). The activity of insulin and other growth factors like IGF-1 are reduced, as are the levels and signaling of testosterone (300). At the same time, catabolic signals such as glucocorticoids, myostatin, NF-kB, and FoxO are upregulated, activating atrophy producing genes, which initiate the physical breakdown of proteins in muscle (301, 302). Obviously, that is all very bad for muscle size and body composition, so let’s take a look at these pathways in more detail. These will be kind of complicated, so some may better visualize and understand by also viewing the attached GRAPHIC LPS and Anabolic Pathways This is simplified, but the anti-anabolic signaling pathways of LPS basically proceed as follows: LPS/TLR-4/TNF-a/ROS DECREASES Insulin&IGF-1 signaling/Akt/mTOR/Protein Synthesis LPS/TLR-4/TNF-a/ROS DECREASES Amino Acid signaling/mTOR/Protein Synthesis LPS/Cortisol/ROS/Myostatin DECREASES Akt/mTOR/Protein Synthesis To reiterate at risk of being repetitive, the body views lipopolysaccharide (aka endotoxin) as an attack. LPS is a ligand of TLR-4, which literally exists to recognize molecular patterns of pathogens and toxins, then subsequently activate the inflammatory immune response in self-defense. This is great, when your body needs to occasionally protect itself. It is very bad when it is constant and chronic because of diet and lifestyle. LPS injections result in a 50% fall in protein synthesis in skeletal muscle, along with a 60-100% increase in muscle protein degradation (303). Decreases in muscle protein content from LPS are equivalent to those with starvation (304). However, the rate of protein synthesis in the liver and plasma proteins, especially albumin and immunoglobulins, is greatly increased to match (305, 306). Basically, amino acids from diet and muscles are being commandeered for the battle (307). You are not going to get that high of LPS levels from dysbiosis of the microbiota, unless you have sepsis inducing food poisoning or the like, but it goes to show how powerful LPS is as an anti-anabolic, pro-catabolic trigger. Obesity and type-2 diabetes are known to be associated with a chronic, low-grade inflammatory state, and this is accompanied by impairment of protein metabolism such as a lack of stimulation of protein synthesis by insulin and amino acids, as well as lower inhibition of proteolysis by the same (308, 309). The protein synthetic response to exercise is blunted in obesity compared to the lean as well (310). Disruption of the mTOR pathway, and its stimulation of protein synthesis, is also seen in these subjects (311) (312). However, chronic excessive energy intake and increased adiposity, without the metabolic disturbances, do not induce any changes in tissue protein synthesis rates, indicating the primacy of inflammatory pathways in these effects (313). LPS diminishes the anabolic sensitivity to BCAAs and EAAs (314, 315). It also reduces IGF-I levels (316). Repeated LPS administration decreases muscle weight and muscle fiber cross sectional area (317). In addition, LPS treatment reduces blood flow in muscle by as much as 70% (318). So, not only are your muscles less sensitive to various anabolic signals, less of those are even getting there. Exercise reduces the LPS receptor, TLR-4, along with LPS induced inflammation (319). Via TLR-4, LPS massively increases TNF-alpha, the next step in the inflammatory equation – and, inhibition of TLR-4 reverses this (320, 321). TNF-alpha is highly involved in muscle wasting and kicks off the ROS cascade that invokes myostatin, NF-kB, and ceramides, which we will get into in a bit (322, 323, 324). LPS induced TNF-alpha increases result in decreased body and skeletal muscle weight, and TNF-alpha shares with LPS an elevated rate of BCAA oxidation (325, 326). LPS promotes TNF-alpha mRNA transcription, with subsequent declines in IGF-1 (327, 328). Direct TNF-alpha administration also lowers IGF-1, along with gastrocnemius weight (329, 330). TNF-alpha completely prevents insulin-mediated augmentation of capillary recruitment and blood-flow as well, inhibiting skeletal muscle glucose uptake by more than half (331). Reducing TLR-4 and TNF-alpha increases the anabolic signal transducer “Akt”, which we will talk a bit about, now (332). Akt You possibly have never even heard of it, but Akt (also known as Protein Kinase is one of the most important molecular signals controlling skeletal muscle mass. It affects both anabolism, through mTOR regulation of protein synthesis, and catabolism, through FoxO regulation of protein degradation (333, 334). Anabolic growth factors such as insulin, IGF-1, and testosterone, as well as factors inhibiting anabolism such as TNF-alpha and myostatin, transmit their cellular signals on hypertrophy and atrophy by altering the activity of Akt and its phosphorylation of its numerous downstream substrates (335). Basically, Akt turns pro-muscle growth targets on, and anti-muscle growth targets off. Genetic activation of the Akt/mTOR pathway causes hypertrophy and prevents atrophy, whereas genetic silencing blocks hypertrophy in vivo (336). Testosterone administration activates Akt signaling (337, 338). It upregulates the insulin-dependent Akt/mTOR signal transduction pathways in an androgen receptor dependent manner (339). Another androgen, Nandrolone, increases IGF-1 expression and its activation of Akt/mTor signaling while decreasing catabolic FoxO transcription (340). Resistance training induced muscle hypertrophy increases Akt and phosphorylation of mTOR, with a parallel drop in FoxO, and detraining does the opposite on all parameters (341). Mechanical overload also induces muscle hypertrophy via activation of Akt and its downstream anabolic pathways (342). LPS decreases Akt, along with its phosphorylation (thus, activation) of mTOR, as well as upregulating catabolic NF-kB and FoxO (343, 344). Increases in TLR-4 and TNF-alpha also downregulate Akt (345). Akt downregulation by TNF-alpha reduces skeletal muscle protein synthesis and increases protein degradation (346). Inflammatory cytokines like TNF-alpha decrease IGF-1’s activation of Akt, subsequently increasing expression of muscle atrophy-related genes (347). Elevated reactive oxygen species (ROS) production by TNF-alpha inhibits Akt/mTOR pathways and upregulates atrophy promoting genes (348, 349). And, as would be expected, ROS directly promote resistance to insulin signaling in skeletal muscle (350, 351). Amino acids and insulin fail to stimulate activation of Akt/mTOR mediated muscle protein synthesis in aged rats, a model of chronic, low-grade inflammation (352). Likewise, insulin resistant subject have reduced muscle Akt phosphorylation and negligible Akt mediated anabolic response to physiological insulin levels (353). mTOR You may be at least somewhat familiar with mTOR, as it is known to mediate increased protein synthesis from BCAAs such as leucine (354). LPS administration reduces phosphorylation of mTOR by Akt in skeletal muscle (355). Activation of TLR-4 by LPS inhibited the Akt/mTOR pathway, decreasing protein synthesis (356). Unlike insulin, amino acid action on mTOR induced protein synthesis is not modulated by Akt (357, 358). LPS also blocks leucine stimulated muscle protein synthesis, independently of Akt (359). Nitric Oxide and Satellite Cells The Akt/mTOR pathway also mediates the upregulation of nitric oxide (NO) by insulin (360, 361). Prolonged exposure to insulin (i.e. insulin resistance) desensitizes this pathway and blunts NO production (362). You probably are familiar with NO, as it is one of the more popular supplement categories, but we will still take a quick look at a bit of data. NO is a key messenger in myogenesis, particular in response to repairing muscle damage, such as from working out (363). It promotes muscle satellite cell activation and proliferation, as well as induction of myogenic genes such as myogenin and follistatin (364, 365). This satellite cell activation is dependent on the Akt/mTOR upregulation of NO production (366). Aging (which is associated with inflammation, hindered insulin signaling, and muscle loss) results in reduced activation and speed of satellite cell migration to half of that of young cells, which is reversed by NO (367, 368). Ceramides Ceramides are reactive lipid species that, for all intents and purposes, behave like reactive oxygen species (ROS) within muscle tissue (369). It is a 2nd messenger in TNF-alpha inflammatory signaling cascades (370). Ceramide accumulation in muscle is higher in obese and aged subjects, concomitant with decreased sensitivity to insulin and its anabolic effects (371, 372). Ceramide also decreases sensitivity of mTOR to amino acid induction of protein synthesis (373). In addition to insulin signaling, it diminishes anabolic responsiveness to IGF-1 by elevating Akt degradation (374, 375, 376). As would be expected, ceramide also reduces glucose uptake and glycogen synthesis, via inhibition of Akt/mTOR (377, 378). Of note, even though we are focusing on the anabolic and anti-catabolic actions when discussing insulin signaling pathways, uptake up glucose and amino acids, as well as glycogen synthesis, are generally increased when insulin sensitivity is increased. These are not divergent pathways. It simply is not our main focus, here. In addition to decreased anabolic activity, the decreased activity of Akt by TNF-alpha and ceramides also takes the breaks off of catabolic signaling via FoxO and NF-kB, promoting muscle atrophy (379, 380). Exercise (surprise, surprise) reduces muscle ceramide content, restoring insulin sensitivity (381). Testosterone The testis barrier basically works exactly the same as the gut barrier, including 1) being susceptible to increased permeability to LPS and inflammatory damage, 2) the enhanced expression of tight junction proteins and improvement of barrier function by bacterial fermentation products such as butyrate, and 3) modulation of all of this by the gut microbiome (382, 383). LPS administration in healthy subjects inhibits testosterone production directly in the Leydig cells of the testes (384, 385). Germ free mice (which do not have bacteria to produce SCFAs) show increased blood-testis-barrier permeability and lower testosterone production, which is fixed with probiotic administration (386), 387, 388). Obesity and metabolic syndrome are associated with lower testosterone levels, along with the low-grade inflammatory state (389, 390). A close relationship exists between the development of a pro-inflammatory state and the decline in testosterone levels, and these are thought to be very much causally linked (391, 392). Finally, heavy endurance exercise training (like marathons and such) is consistently associated with persistent low-grade systemic inflammation together with reduced free and total testosterone levels (393, 394). You are no doubt familiar with the positive effects of testosterone on muscle, so we won’t get into that, but I will just note that testosterone inhibits the LPS/TLR-4/TNF-alpha inflammatory, anti-anabolic/pro-catabolic pathways (395). LPS and Catabolic Pathways This is simplified a bit, once again, but LPS induced increases in catabolism basically proceed as follows: LPS/TLR-4/TNF-a/ROS INCREASES NF-kB/Atrogenes/Muscle Breakdown LPS/Cortisol/Myostatin DECREASES Akt INHIBITION OF FoxO/Atrogenes/Muscle Breakdown LPS/TLR-4/TNF-a/ROS/NF-kB<->Myostatin<->ROS<->NFKb and FoxO/Atrogenes/Muscle Breakdown Just like with inhibition of anabolic signaling, LPS escapes the gut, increasing inflammatory cytokines like TNF-alpha and reactive oxygen species throughout the body. This elevates NF-kB, which then triggers atrophy promoting genes (atrogenes) that subsequently induce the physical breaking down of proteins in muscle tissue. LPS also amplifies cortisol release, which increases myostatin, which inhibits Akt. This takes the breaks off of FoxO activated atrogene expression which, again, subsequently induces the physical breaking down of proteins in muscle tissue (396). There is also a feed forward myostatin/TNF-alpha/ROS/NF-kB loop, where they all increase each other, which results in activation of both NF-kB and FoxO (397, 398). NF-kB and FoxO, together, account for 95% of muscle fiber atrophy, so let’s take a look at some data on those two (399). NF-kappaB Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-kB), along with FoxO, is one of the two primary atrogene activating pathways at the end of the LPS induced catabolic chain (400). It is induced by reactive oxygen species generated by TNF-alpha, and blocking ROS production prevents its activation by LPS administration (401, 402). Blocking TLR-4, upstream of TNF-alpha, also inhibits NF-kB (403). NF-kB is implicated in various models of atrophy (404, 405). It is significantly elevated, along with TNF-alpha, in myocytes from obese type-2 diabetics (406). Insulin resistant subjects display higher elevations in NF-kB in response to LPS than normal glucose tolerant ones (407). The resistance to the anabolic effects of exercise seen in aging is also associated a rise in NF-κB activity (408). Interestingly, the increases seen with aging, and the associated inflammation, is normalized with lifetime calorie restriction (known to be anti-inflammatory) in animal models (409, 410). Though, it increases catabolism in both slow-twitch and fast-twitch muscle fibers, NF-kB is more highly expressed in slow-twitch fibers (411, 412). It is particularly noted in disuse atrophy, so hopefully you already have that part of it covered with exercise (413, 414). It also inhibits Akt, perhaps via myostatin, which would ultimately also induce catabolic FoxO, which we will talk about next (415). Thus, its indirect negative effects of NF-kB on muscle may be even more important than the direct ones. FoxO The Forkhead Box O (FoxO) family is the second major atrogene activating pathway at the end of the LPS induced catabolic chain. It is induced by cortisol and myostatin, and it results primarily in atrophy of fast-twitch fibers (416). It is stimulated by ROS, likely through myostatin (417). FoxO is negatively regulated by Akt, as we mentioned previously (418, 419). When Akt’s inhibition of FoxO is removed, atrogenes are induced and loss of muscle mass follows (420, 421). It is inhibited by both insulin and IGF-1 signaling via Akt (422, 423). FoxO is likely the more important catabolic pathway vs. NF-kB, both because of the preferential fast-twitch degradation and because activation occurs in more common atrophy promoting situations due to the nexus with the ubiquitous Akt. Blockade of FoxO also prevents muscle atrophy from glucocorticoids, which leads us to our next segment (424). Cortisol Cortisol strongly activates both anti-anabolic (via inhibition of insulin signaling) and catabolic (via myostatin and FoxO) pathways, but we are putting it in the catabolic section. Being a stress hormone, it is triggered by not just perceived emotional stress, but energetic stress, such as with starvation, or for our purposes, the metabolic stress of the LPS induced inflammatory response (425). Before we get into the negative effects of gut dysbiosis on cortisol in relation to muscle, it should be mentioned that there exists a bidirectional communication system between the gastrointestinal tract and the brain (426, 427). A full treatment of the Gut-Microbiota-Brain axis is well beyond our scope, but in addition to dysbiosis and inflammation messing up the stress axis, stress and anxiety are signaled from the brain to the gut and mess it up, as well (428, 429). In other words, it is a feed-forward vicious cycle. Getting back to LPS and cortisol… As a systemic immunological stressor, LPS invokes a prolonged activation of the hypothalamic-pituitary-adrenal (HPA) axis via cytokines such as TNF-alpha, ultimately increasing cortisol release from the adrenals (430, 431). Cortisol is anti-inflammatory, and synthetic glucocorticoids are well known as being useful for this purpose (432). This anti-inflammatory activity, from an evolutionary perspective, likely serves as a mitigating factor in fever/ROS induced cellular toxicity (433, 434). Indeed, impairment of the HPA axis results in greatly increased lethality from LPS/endotoxic shock (435). Getting to cortisol and muscle, the purpose of cortisol with cellular stress such as from the LPS inflammatory cascade is to rapidly mobilize carbohydrate, fat, and protein stores to provide energy for the fight (436). With inflammation, protein is particularly in demand, as it is necessary for synthesis of acute phase reactants, which are a group of proteins that modulate the immune response (437). Thus, muscle protein synthesis is suppressed while breakdown is activated to provide said protein (438). This response also increases gluconeogenesis from amino acids preferentially over fatty acid oxidation as fuel to quickly provide ATP for increased energetic demands (439). We’ve basically mentioned all of that before, but it is worth repeating, as it is the “Why” on something meant to protect you going so terribly wrong. Cortisol quickly initiates muscle fiber atrophy, as IGF-1 and insulin signaling are blunted while myostatin is increased (440, 441, 442). This is mediated, downstream, through the Akt/mTOR and Akt/FoxO pathways, respectively (443, 444). Even worse, this atrophy is preferential toward high energy demanding fast-twitch fibers (445, 446). Glucocorticoids also initiate NF-κB activation, likely through the myostatin-ROS pathway mentioned earlier (447). In addition to insulin resistance through Akt/mTOR inhibition, glucocorticoids also reduce the activity of GLP-1, which we will talk about in a bit (448) Lactobacillus has been found to block restraint stress induced increases in LPS and cortisol (449). Interestingly, though cortisol inhibits mTOR’s anabolic activity, mTOR modulates glucocorticoid receptor function, counteracting its catabolic effects (450). So, more good news on BCAAs. Myostatin Myostatin is the major mediator in cortisol’s negative effects on muscle size, so we will give it its own little mini-section. It is upregulated by glucocorticoid administration and stress (451, 452). This stimulates muscle atrophy through a cascade of signals that includes activation of FoxO and NF-kB (453, 454, 455). Myostatin overexpression results in an atrophic phenotype with fast-twitch fibers being most sensitive (456). Myostatin also inhibits Akt, thus insulin and IGF-1 anabolic signaling through mTOR (457, 458, 459). Part 5 finale on Thursday, June 28th