Muscle Inflammation is Necessary for Muscle Hypertrophy

Muscle Inflammation is Necessary for Muscle Hypertrophy
by:Robbie Durand, M.A., C.S.C.S.

Wolverine from the movie is quite possibly the ultimate soldier. He has adamantium claws that can turn anyone that pisses him off into chop suey, an unbreakable skeleton, and a bad attitude to match. His primary mutant power is an accelerated healing factor that regenerates damaged or destroyed areas of his body far beyond the capabilities of an ordinary human and renders him immune to physical damage. Wouldnt it be nice if we had an accelerated healing factor which would allow us to go to the gym and have an intense workout with some heavy negatives and not be sore? That sore feeling you get after an intense workout is because you damaged skeletal muscle and your bodys own healing factors are regenerating muscle fibers. Believe it or not your immune system plays an important part in the role of building muscle; anything that compromises its function can impede muscle growth.

Wolverines accelerated healing power allows him to regenerate damaged tissue instantly. Our immune system, plays a vital role in repairing
damaged muscle, the use of NSAIDS which may reduce pain is actually counterproductive to increasing muscle mass!

The Role of Macrophages in Muscle Repair and Growth

When resistance exercise involves heavy eccentric muscular contractions (lowering the weight), it is associated with overloading skeletal muscle that is, the force requirement of the muscle exceeds what it is accustomed to and results in injury to skeletal muscle. It has traditionally been felt that the events following the initial injury, including inflammation, are necessary for optimal repair and growth of new muscle. Exercise-induced muscle damage stimulates an acute-phase inflammatory response, which includes infiltration into skeletal muscle by macrophages1. Macrophages (Greek: big eaters) are cells within the tissues that originate from specific white blood cells. One important role of macrophage is the removal of damaged tissue by heavy resistance exercise. Repairing damaged muscle cells is an important function of macrophages in the early stages of muscle damage and inflammation. This inflammatory response coincides with muscle repair, regeneration, and growth, which involves the activation of satellite cells (satellite cell activation is essential for muscle hypertrophy). The number of macrophages per square millimeter of muscle tissue is increased after heavy eccentric exercise compared to concentric exercise (lifting the weight) which may play an important role as to why eccentric contractions produce greater muscle hypertrophy2. Macrophages are also able to promote muscle growth and repair. In vitro studies (test tubes studies) show macrophages can increase muscle cell growth factors3,4, which indicates a role for macrophage-derived factors in muscle growth.

What happens if you suppress your Healing Factor?

The healing process that occurs during rest is an important adaptation to building muscle. You may be sore as hell after a heavy leg workout but that means your shocking your muscles into new growth. The inflammatory process although painful for a bodybuilder is an essential part of the muscle growth process. For instance, mediators such as IGF-1 are stimulated by the release of inflammatory cells5. So what happens if you suppress macrophages after injury? Just like Wolverine in the movies, if you lose your healing factors youre screwed in terms of building muscle. Researchers injected mice with an antibody that reduced macrophage concentrations after a couple of days of muscle overloading (86% reduction in macrophage concentration) and found that muscle fiber repair and growth was significantly impaired after muscle overload6. Macrophage-depletion also reduced muscle regeneration and prevented growth of muscle fibers that normally occurs with muscle overload. These findings suggest that macrophage first invades injured muscle serves to remove cellular debris, after which the subsequent invasive population participates in repair, regeneration and growth.

A strain of mice was recently genetically engineered to test the hypothesis of macrophage invasion to the site of injury is important for muscle regeneration and growth. A strain of mice was bred to be deficient in a protein called MCP-1 (Monocyte chemotactic protein-1), a potent activator for macrophage invasion and inflammation. Researchers damaged muscle fibers of these mice and compared them to normal mice; the mice that had impaired muscle macrophage activity due to a MCP-1 deficiency had impaired muscle regeneration and growth. The researchers speculated that the impaired muscle regeneration was due to macrophages not being able to repair the damaged muscle. Remember, muscle growth takes place during the recovery phase, lifting weights only serves as the stimulus. The research suggests that unless the damaged muscle fiber becomes invaded by macrophages and other repair mediators, it becomes stagnant and muscle repair is halted and the muscle tissue stays damaged. Interestingly, macrophages can increase nitric oxide which expands blood vessels and open up the muscle tissue to blood flow which allows for more macrophages to repair damaged muscle tissue10.

NSAIDS Suppress Muscle Growth

You may feel the urge to take an Aleve or Ibuprofen tablet after an intense workout to reduce muscle soreness or you may suffer from a chronic knee or elbow injury from years of heavy lifting but only take NSAIDS when absolutely necessary. According to a new study in Medicine & Science in Sports & Exercise, taking ibuprofen can inhibit muscle hypertrophy. In the study, rats had surgeries performed in which their leg muscles are chronically overloaded to cause muscle hypertrophy. One group of rats received ibuprofen while the other group received nothing. At the end of the study, rats that were administered ibuprofen had a whopping 50% reduction in muscle hypertrophy8. Another study reported that when Non Steroidal Anti-Inflammatory Drugs (NSAIDS) were examined after muscle injury, not only was satellite cell (muscle stem cells) activity in muscle inhibited by their was a increase in myostatin (inhibits muscle growth) production. Examples of NSAIDs include Aspirin, indomethacin (Indocin), ibuprofen (Motrin), naproxen (Naprosyn), piroxicam (Feldene), and nabumetone (Relafen). Recent research suggests that regular use of NSAIDS or COX-2 inhibitors such as Celebrex or Vioxx can significantly reduce muscle hypertrophy by reducing expression of the enzyme COX-2. In conjunction with other research, the COX-2 pathway serves as an important mediator of the inflammation response after exercise serving to repair damaged tissue and is an essential for muscle hypertrophy to occur.

More recent findings have shown cyclooxygenase-2 (COX-2) oral administration of COX-2 inhibitors can slow muscle regeneration and reduce muscle growth after acute injury of muscle7. Interestingly, mice that are genetically engineered to be COX-2 deficient showed less macrophage invasion of injured muscle during regeneration7, which may indicate that macrophages normally promote muscle cell proliferation and muscle regeneration following injury. Alternatively, COX-2 may have a direct effect on muscle cells to affect muscle repair. Additionally, it is well known that in order to build muscle there must be an increase in muscle protein synthesis rates. Studies have reported that if the maximal dosage of ibuprofen or acetaminophen is taken before exercise that protein synthesis rates are blunted9. In that study, subjects performed 10 sets of eccentric exercise performed at 120% of a 1-RM, subjects that received a placebo had average of 76% increase in protein synthesis rates, whereas the subjects whom received either ibuprofen or acetaminophen had no increase in protein synthesis.

In conclusion, dont take any NSAIDS unless its absolutely necessary for alleviating pain. NSAIDS reduce muscle protein synthesis and inhibit muscle hypertrophy. Muscle inflammation and repair is an essential part of hypertrophy process, and although you may be sore as hell, the benefits you will reap from the pain are bigger and stronger muscles.


1. Fielding, RA, Manfredi TJ, Ding W, Fiatarone MA, Evans WJ, and Cannon JG. Acute phase response in exercise. III. Neutrophil and IL-1 accumulation in skeletal muscle. Am J Physiol Regulatory Integrative Comp Physiol 265: R166-R172, 1993.

2. Stupka N, Tarnopolsky MA, Yardley NJ, Phillips SM. Cellular adaptation to repeated eccentric exercise-induced muscle damage. J Appl Physiol. 2001 Oct;91(4):1669-78.

3. Cantini M & Carraro U (1995). Macrophage-released factor stimulates selectively myogenic cells in primary muscle culture. J Neuropathol Exp Neurol 54, 121-128.

4. Cantini M, Giurisato E, Radu C, Tiozzo S, Pampinella F, Senigaglia D, Zaniolo G, Mazzoleni F & Vittiello L (2002). Macrophage-secreted myogenic factors: a promising tool for greatly enhancing the proliferative capacity of myoblasts in vitro and in vivo. Neurol Sci 23, 189-194.

5. Musaro A, McCullagh K, Paul A, Houghton L, Dobrowolny G, Molinaro M, Barton ER, Sweeney HL, Rosenthal N. Localized Igf-1 transgene expression sustains hypertrophy and regeneration in senescent skeletal muscle. Nat Genet. 2001 Feb;27(2):195-200.

6. Tidball JG, Wehling-Henricks M. Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo. J Physiol. 2007 Jan 1;578(Pt 1):327-36.

7. Bondesen BA, Mills ST, Kegley KM, Pavlath GK. The COX-2 pathway is essential during early stages of skeletal muscle regeneration. Am J Physiol Cell Physiol. 2004 Aug;287(2):C475-83.

8. Soltow QA, Betters JL, Sellman JE, Lira VA, Long JH, Criswell DS. Ibuprofen inhibits skeletal muscle hypertrophy in rats. Med Sci Sports Exerc. 2006 May;38(5):840-6.

9. Trappe TA, Fluckey JD, White F, Lambert CP, Evans WJ. Skeletal muscle PGF(2)(alpha) and PGE(2) in response to eccentric resistance exercise: influence of ibuprofen acetaminophen. J Clin Endocrinol Metab. 2001 Oct;86(10):5067-70.

10. Nguyen HX, Tidball JG. Interactions between neutrophils and macrophages promote macrophage killing of rat muscle cells in vitro. J Physiol. 2003 Feb 15;547(Pt 1):125-32. Epub 2002 Dec 20.

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