MUSCLE DISEASES
Ed Friedlander, M.D., Pathologist
scalpel_blade@yahoo.com

Cyberfriends: The help you're looking for is probably here.

Welcome to Ed's Pathology Notes, placed here originally for the convenience of medical students at my school. You need to check the accuracy of any information, from any source, against other credible sources. I cannot diagnose or treat over the web, I cannot comment on the health care you have already received, and these notes cannot substitute for your own doctor's care. I am good at helping people find resources and answers. If you need me, send me an E-mail at scalpel_blade@yahoo.com Your confidentiality is completely respected.

DoctorGeorge.com is a larger, full-time service. There is also a fee site at www.afraidtoask.com.


If you have a Second Life account, please visit my teammates and me at the Medical Examiner's office.

Freely have you received, give freely With one of four large boxes of "Pathguy" replies.

I'm still doing my best to answer everybody. Sometimes I get backlogged, sometimes my E-mail crashes, and sometimes my literature search software crashes. If you've not heard from me in a week, post me again. I send my most challenging questions to the medical student pathology interest group, minus the name, but with your E-mail where you can receive a reply.

Numbers in {curly braces} are from the magnificent Slice of Life videodisk. No medical student should be without access to this wonderful resource. Someday you may be able to access these pictures directly from this page.

I am presently adding clickable links to images in these notes. Let me know about good online sources in addition to these:

Freely have you received, freely give. -- Matthew 10:8. My site receives an enormous amount of traffic, and I'm handling about 200 requests for information weekly, all as a public service.

Pathology's modern founder, Rudolf Virchow M.D., left a legacy of realism and social conscience for the discipline. I am a mainstream Christian, a man of science, and a proponent of common sense and common kindness. I am an outspoken enemy of all the make-believe and bunk that interfere with peoples' health, reasonable freedom, and happiness. I talk and write straight, and without apology.

Throughout these notes, I am speaking only for myself, and not for any employer, organization, or associate.

Special thanks to my friend and colleague, Charles Wheeler M.D., pathologist and former Kansas City mayor. Thanks also to the real Patch Adams M.D., who wrote me encouragement when we were both beginning our unusual medical careers.

If you're a private individual who's enjoyed this site, and want to say, "Thank you, Ed!", then what I'd like best is a contribution to the Episcopalian home for abandoned, neglected, and abused kids in Nevada:

I've spent time there and they are good. Write "Thanks Ed" on your check.

Help me help others

My home page
More of my notes
My medical students

Especially if you're looking for information on a disease with a name that you know, here are a couple of great places for you to go right now and use Medline, which will allow you to find every relevant current scientific publication. You owe it to yourself to learn to use this invaluable internet resource. Not only will you find some information immediately, but you'll have references to journal articles that you can obtain by interlibrary loan, plus the names of the world's foremost experts and their institutions.

Alternative (complementary) medicine has made real progress since my generally-unfavorable 1983 review linked below. If you are interested in complementary medicine, then I would urge you to visit my new Alternative Medicine page. If you are looking for something on complementary medicine, please go first to the American Association of Naturopathic Physicians. And for your enjoyment... here are some of my old pathology exams for medical school undergraduates.

I cannot examine every claim that my correspondents share with me. Sometimes the independent thinkers prove to be correct, and paradigms shift as a result. You also know that extraordinary claims require extraordinary evidence. When a discovery proves to square with the observable world, scientists make reputations by confirming it, and corporations are soon making profits from it. When a decades-old claim by a "persecuted genius" finds no acceptance from mainstream science, it probably failed some basic experimental tests designed to eliminate self-deception. If you ask me about something like this, I will simply invite you to do some tests yourself, perhaps as a high-school science project. Who knows? Perhaps it'll be you who makes the next great discovery!

Our world is full of people who have found peace, fulfillment, and friendship by suspending their own reasoning and simply accepting a single authority that seems wise and good. I've learned that they leave the movements when, and only when, they discover they have been maliciously deceived. In the meantime, nothing that I can say or do will convince such people that I am a decent human being. I no longer answer my crank mail.

This site is my hobby, and I do not accept donations, though I appreciate those who have offered to help.

This page was last updated February 9, 2008.

During the thirteen years my site has been online, it's proved to be one of the most popular of all internet sites for undergraduate physician and allied-health education. It is so well-known that I'm not worried about borrowers. I never refuse requests from colleagues for permission to adapt or duplicate it for their own courses... and many do. So, fellow-teachers, help yourselves. Don't sell it for a profit, don't use it for a bad purpose, and at some time in your course, mention me as author and KCUMB as my institution. Drop me a note about your successes. And special thanks to everyone who's helped and encouraged me, and especially the people at KCUMB for making it possible, and my teaching assistants over the years.

Whatever you're looking for on the web, I hope you find it, here or elsewhere. Health and friendship!

We comply with the HONcode standard for trustworthy health
information:
verify here.

PicoSearch
 Help

More of Ed's Notes: Ed's Medical Terminology Page

Perspectives on Disease
Cell Injury and Death
Accumulations and Deposits
Inflammation
Fluids
Genes
What is Cancer?
Cancer: Causes and Effects
Immune Injury
Autoimmunity
Other Immune
HIV infections
The Anti-Immunization Activists
Infancy and Childhood
Aging
Infections
Nutrition
Environmental Lung Disease
Violence, Accidents, Poisoning
Heart
Vessels
Respiratory
Red Cells
White Cells
Coagulation
Oral Cavity
GI Tract
Liver
Pancreas (including Diabetes)
Kidney
Bladder
Men
Women
Breast
Pituitary
Thyroid
Adrenal and Thymus
Bones
Joints
Muscles
Skin
Nervous System
Eye
Ear
Autopsy
Lab Profiling
Blood Component Therapy
Serum Proteins
Renal Function Tests
Adrenal Testing
Arthritis Labs
Glucose Testing
Liver Testing
Porphyria
Urinalysis
Spinal Fluid
Lab Problem
Quackery
Alternative Medicine (current)
Alternative Medicine (1983)
Preventing "F"'s: For Teachers!
Medical Dictionary

Courtesy of CancerWEB

Musculoskeletal
Photos, explanations, and quiz
Indiana U.

Muscle pathology
Nice pictures
Virginia Commonwealth University

Musculoskeletal
Utah cases for path students
Juliana Szakacs MD

Soft Tissue and Muscle
Iowa Virtual Microscopy
Have fun

Clinical Musculoskeletal Pathology
Go through IMC
You need to join first.
Pittsburgh Illustrated Case

"Why I Support Amateur Boxing"
Position paper by Ed
This is something about which
reasonable people can differ.

Musculoskeletal Pathology
Virginia Commonwealth U.
Great pictures

Musculoskeletal Disease
Mark W. Braun, M.D.
Photomicrographs

Myopathies I
From Chile
In Spanish

Myopathies II
From Chile
In Spanish

Muscle Pathology
Good photos and text
Neuropathology Web

QUIZBANK Muscle & soft tissue (all except #'s 55-61)


Dino LaPorte
Former path TA

INTRODUCTION

{14614} skeletal muscle, histology
{20723} skeletal muscle, histology
{44101} skeletal muscle, ultrastructure
{44116} mitochondrion & sliding filaments
{44110} section of myofilaments
{18639}
{18643}
{18644}
{18665}

{14381} normal; NADH stain with type I fibers dark, type II fibers light
{14418} normal; ATPase stain with type I fibers dark, type II fibers light

REACTIONS OF MUSCLE CELLS

{14430} disuse or glucocorticoid atrophy, type II fibers

{14414} degenerating fibers, early Duchenne's

Duchenne's muscular dystrophy
Autopsy view of calf
KU Collection

{14393} several target fibers

{14421} several angular fibers

Neurogenic atrophy
Tom Demark's Site

{25526} split fiber in early muscular dystrophy

    Fibrosis (endomysium, perimysium) often follows inflammation and/or atrophy. Fatty ingrowth ("fatty infiltration", not to be confused with "fatty change") is often common in end-stage muscle. With a few exceptions, neither change is very helpful diagnostically.

    Future clinicians: When doing a muscle biopsy, remember:

    (1) Muscle biopsies hurt. Don't do muscle biopsies for "academic" curiosity. If you decide to do the biopsy, warn your patient.

    (2) A muscle biopsy in Duchenne's will result in fibrosis and contracture of the muscle; suspected Duchenne's is a relative contraindication to the procedure.

    (3) Select a muscle that is mildly, but definitely, involved. The pathology will show best here. (If a muscle isn't weak, the histology won't be abnormal. If the muscle is mostly fibrous tissue and fat, giving a specific diagnosis is probably impossible.

    * (4) Don't biopsy near a tendon, or the pathologist may not know how to interpret the "fibrosis", uneven fiber size, and increased nuclei.

    (5) Don't biopsy recent sites of injections or electromyography needle insertions.

    * (6) The deltoid has an unusual connective tissue pattern, so let the pathologist know if this is your biopsy site.

    (7) Keep the muscle fragment from contracting after biopsy. We'll give you a clamp.

    (8) Today, the diagnosis of each of the common genetic muscle diseases is made on immunohistochemistry, usually on frozen sections, though with newer antibodies, paraffin-embedded tissue can be used (J. Clin. Path. 54: 517, 2001; fiber typing J. Clin. Path. 55: 375, 2002).

MYASTHENIA GRAVIS

    In this disease, which is fairly common especially among young women, polyclonal antibodies attack the acetylcholine receptor (* bungarotoxin binding site) of the post-synaptic membrane of the neuromuscular junction. This is unwholesome, since binding of acetylcholine is blocked, and receptors are degraded too rapidly.

    Interestingly, about 30% of these patients have a thymoma, and most of the rest have thymic hyperplasia (i.e., prominent germinal follicles in the thymus gland).

      Most thymomas express acetylcholine receptor epitopes on the surfaces of the neoplastic cells (Lancet 339: 707, 1992; Am. J. Path. 148: 1359 & 1839, 1996). We can suppose for now that this is what triggers the disease.

        * Several other anti-muscle autoantibodies (anti-titin, anti-ryanodine-receptor, anti-striational) also commonly turn up in these people (Muscle & Nerve 21: 329, 1998; Arch. Neuro. 62: 442, 2005). Again, it's supposed to be molecular mimicry. "Thymomatous MG" and "MG with titin antibodies" now are considered separate entities: Arch. Neuro. 64: 1729, 2007).

        * The thymoma may be too small to see on scan: Chest 131: 847, 2007.

        Occasional patients lack autoantibodies against the acetyl-choline receptor; these people usually have antibodies against muscle-specific kinase (anti-MuSK) instead, and do not benefit from thymectomy (Brain 126: 2304, 2003).

      As with other autoimmune diseases, patients often have a second serious autoimmune disease. Look for Hashimoto's, lupus, rheumatoid arthritis, autoimmune thyroid disease.

      * Of course the antibody can cross the placenta, and weaken the unborn child.

      Extended thymectomy (i.e., be sure you get the little bits of thymus a few cm away from where the gland is supposed to be located) seems to be the procedure of choice nowadays (Ann. Thoracic Surg. 62: 853, 1996).

    Patients suffer from weakness, and tire easily. The disease usually begins in the eyes (droopy "ptotic" eyelids, double vision). You'll learn about the "Tensilon test" on rotations. Like most autoimmune diseases, myasthenia gravis is a disease of exacerbations and remissions, and thanks to the "ICU", today's patients usually die of something else.

      This is not an anatomic pathologist's disease. In a minority of patients clusters of lymphocytes (* "lymphorrhages") appear around the motor end plates (Arch. Path. Lab. Med. 112: 934, 1988; Neurology 41: 1497, 1991; Neurology 38: 1173, 1988).

      * Aristotle Onassis, who married Jack Kennedy's widow Jackie, died of myasthenia gravis.

      Probably the ability to get myasthenia gravis is polygenic. Particular alleles at the TNF-alpha, TNF-beta, FcGamma receptor IIa, and interleukin 10 loci all run with the disease (Arch. Neuro. 64: 1729, 2007).

    Other myasthenic syndromes: In addition to some genetic NMJ problems (Arch. Neuro. 56: 163, 1999), you need to remember the Eaton-Lambert syndrome, a weakness syndrome typically seen with oat cell carcinoma of the lung, though sometimes alone. These patients make an autoantibody against calcium channels (NEJM 332: 1467, 1995 review) that blocks release of acetylcholine itself.

MUSCLE CHANGES IN PERIPHERAL NERVE DISEASE

    Denervation (i.e., lower motor neuron) changes in muscle occur only if the axon itself is damaged. (Contrast "demyelinating disease" of peripheral nerves, which leaves muscle unchanged.)

    Partially damaged nerve is the site of axonal sprouting, with axons from surviving neurons growing into the empty spaces once occupied by other axons. Since the current axon supplying a muscle cell determines whether it is a type I or a type II fiber, the redistribution of a diminished number of axons will result in type grouping of fibers, pathognomonic (in humans) of denervation-reinnervation.

{14429} denervation-reinnervation pattern with type grouping; compare normal
{14418}

Tetanus with denervation

Yutaka Tsutsumi MD

Type grouping
Tom Demark's Site

    If the disease process continues, and the ability of axons to be replenished is reduced, look for group atrophy of muscle fibers. Sometimes you may see target fibers. Late in the disease, expect to see some myopathic changes, too.

{14353} neurogenic atrophy

    Noteworthy causes of neurogenic atrophy include amyotrophic lateral sclerosis and a variety of other diseases. If denervation is rapid, muscle cells may twitch repetitively due to increased sensitization to acetylcholine, producing fasciculations.

      Werdnig-Hoffman disease ("infantile spinal muscle atrophy") is an autosomal recessive disease of anterior horn cells that produces extremely floppy babies, progressing to death in the first year (there are variants with longer survival). Histology shows atrophic groups of type I and type II fibers and occasional clusters of huge type I fibers. It results from loss of the SMN ("survival motor neuron") genes; other alleles produce other spinal muscle atrophy diseases.

{14372} Werdnig-Hoffman disease
{14375} Werdnig-Hoffman disease
{14403} Werdnig-Hoffman disease

        * Sodium butyrate for SMA... well, it works in the knockout mouse (Proc. Nat. Acad. Sci. 98: 9808, 2001).

      Kugelberg-Welander disease ("the mild counterpart of Werdnig-Hoffman", SMA III) is caused by another allele at the Werdnig-Hoffman locus. It is a milder disease. All you'll see on muscle biopsy is type-grouping and atrophy.

{14380} Kugelberg-Welander disease (note poor muscular development)
{14377} Kugelberg-Welander disease (Gower's sign like in Duchenne's; see below)

      Charcot-Marie-Tooth disease features neurogenic-type atrophy of the leg muscles, especially the calves ("champagne-bottle legs").

{14413} Charcot-Marie-Tooth disease, adult
{14407} Charcot-Marie-Tooth disease, kid
{14429} type grouping, this was a case of Charcot- Marie-Tooth disease

    In upper motor neuron disease, of course, all you will see is widespread fiber atrophy, mostly of type II cells.

MUSCULAR DYSTROPHY

    Introducing genetic disease of muscle

      This is a group of hereditary myopathies, considered together by custom. ("Dystrophy" is a traditional, basically meaningless word.) Short review Lancet 359: 687, 2002.

      Common to these diseases is atrophy and loss of muscle fibers in the absence of nerve disease. Exactly how this happens is only now becoming clear, as the various proteins involved prove to form a membrane complex that gives strength and structure to the muscle cell.

      Now is a good time to mention that, for a given locus, different mutations may give different syndromes. For example, a mutated gene for the calcium channel that is the receptor for ryanodine can produce limb-girdle dystrophy, malignant hyperthermia, central core disease, a dilated cardiomyopathy, or idiopathic cardiac rhythm problems (J. Clin. Inv. 115: 2033, 2005; especially sudden drowning Mayo Clin. Proc. 80: 596, 2005).

      It's also a good time to mention that apparently healthy people with chronically elevated creatine kinase levels and who do not exercise usually have a "forme fruste" of one of the myopathies, with abnormal muscle biopsy (Neurology 66: 1585, 2006). Biopsy and/or gene-screeen if the patient is truly curious.

      The kid who is "just not trying in gym class" may be singled out for abuse from teachers and peers for years before a muscle disease is found.

    Duchenne's muscular dystrophy ("Jerry Lewis's kids")

      This is a common (one male in 3500), sex-linked recessive trait. One third of cases are new mutations, and no population group is without these people. The fundamental lesion is a lack of dystrophin, an inner-sarcolemmal cytoskeletal component homologous to spectrin and actin, which appears to strengthen muscle cells and keep them from popping when overworked (Nature 349: 69 & 243, 1991; Proc. Nat. Acad. Sci. 90: 3710, 1993). The gene's on Xp21.

      Although the children appear normal at birth, the muscle is already abnormal, and the problem becomes obvious in early childhood. These boys have symmetric weakness, and must resort to unusual methods to stand up ("Gower's sign"). Fatty ingrowth produces the characteristic "pseudohypertrophy of the calves". Boys become wheelchair-bound by their early teens.

      About 1/3 of these boys are mentally retarded as a result of involvement of a portion of the locus that also involves a brain protein. Although results are conflicting, the allele seems to be the determining factor (Neurology 55: 559, 2000). Cardiomyopathy is also common (cardiomyopathy-only allele Circulation 87: 1854, 1993), and is a problem even for female carriers (JAMA 275: 1335, 1996).

      The pathologist sees various myopathic changes, notably degeneration with phagocytosis and regeneration attempts along the muscle fibers. Even in muscles that are not yet weak, each fiber is usually ringed by fibrous tissue. As the necrosis predominates, the fibers are replaced by fat and scar tissue. The healthier fibers undergo hypertrophy, producing striking variability in the sizes of fibers. Myofiber types are poorly defined.

{14443} Duchenne's, kid
{14446} Duchenne's, kid
{14449} Duchenne's; Gower's sign
{14408} Duchenne's, early, dark-staining fibers are dying
{14411} Duchenne's, classic histopathology
{09036} Duchenne's, biopsy; trichrome stain (i.e., muscle red, fibrosis blue)

      For some reason, affected boys and their carrier mothers have markedly elevated creatine kinase. Electron microscopists see breaks in the sarcolemma and the CK is probably leaking out here.

      A woman carrying Duchenne's may be affected due to unfortunate lyonization. By contrast, fortunate lyonization may produce a normal creatine kinase, obscuring the carrier state. Of course, normally-lyonized carriers show immunostaining for dystrophin around about half of their myofibers (NEJM 321: 398, 1989). A Turner's woman or testicular-feminization "woman" can have the disease.

      * Autosomal recessive syndromes indistinguishable clinically from Duchenne's are rare, but do occur (Am. J. Hum. Genet. 45: 63, 1989; Neurology 45: 768, 1995; Arch. Dis. Child. 64: 1501, 1989; adhalin deficiency J. Clin. Invest. 96: 1202, 1995).

      Caring for the whole person with Duchenne's requires knowledge, skill, and wisdom: Neurology 39: 475, 1989. Gene therapy for Duchenne's has been a challenge because the molecule is so large (Nat. Med. 8: 253, 2002; Nat. Med. 9: 997, 2003). Manipulating circulating stem cells works in mice: J. Clin. Inv. 114: 192, 2004. Duchenne's patients have been maintained on respirators for as long as 30 years (Chest 123: 1307, 2003; don't do something like this to me).

      * Myoblast transfer for Duchenne's, which works in an animal model, isn't working in people yet. For some reason, the myoblasts simply decide to die when introduced into the human body. NEJM 333: 838, 1995 was the last major review, but stay tuned.

      * Creatine for Duchenne's: seems to help. Neurology 62: 1771, 2004.

    Becker's muscular dystrophy

      "Another sex-linked muscular dystrophy", caused by milder abnormal alleles at the Duchenne's locus. "Becker's" is defined to be "Duchenne's" in which patients can still walk by their 16th birthday. It's less common than Duchenne's: Lancet 337: 1022, 1991; the cardiomyopathy Am. Heart J. 132: 642, 1996.

      The problem in most cases is that dystrophin, though present, is mutated into a less-effective form. Dystrophin has several domains that do different things, and Becker's is very heterogeneous. For a recent review, see Brain 125: 4, 2002.

{14473} Becker's (I think; pseudohypertrophy of calves)
{14467} Becker's (I think; pseudohypertrophy)
{14470} Becker's (I think; pseudohypertrophy)

Becker's
Heart

Becker's muscular dystrophy
WebPath Case of the Week

      * Tunisian autosomal recessive muscular dystrophy resulting from dystrophin-binding glycoprotein deficiency: Nature 359: 320, 1992.

    Emery-Dreifuss muscular dystrophy is a mild disease cause by lack of a protein called "emerin" on the nuclear (rather than the sarcoplasmic) membrane (gene Nat. Gen. 12: 252 & 264, 1996; a dominant locus at lamin A/C Brain 129: 996, 2006). The worst problem is the cardiomyopathy.

{27271} Emery-Dreifuss
{27274} Emery-Dreifuss
{27277} Emery-Dreifuss
{27280} Emery-Dreifuss
{27283} Emery-Dreifuss
{27352} Emery-Dreifuss

    Myotonic dystrophy

      This is an autosomal dominant (* chromosome 19: q13.2-13.3, cloned: Science 255: 1253 & 1256, 1992; protein is "myotonin" Science 260: 235, 1993), variably expressed because of other genes, affecting several systems. In some communities, it is as common as Duchenne's.

      Patients have:

      • weakness, starting in the facial muscles (tiny chins and temples, etc.), eventually atrophy of most muscle groups
      • grip myotonia, with difficulty letting go of keys, handshakes, etc.
      • percussion myotonia (muscles tighten when you rub then)
      • frontal baldness and testicular atrophy (men)
      • a distinctive face ("carp mouth")
      • heart disease
      • early dementia (sometimes)
      • cataracts
      • cardiomyopathy (pathologists see Neurology 63: 2404, 2004; the histology is nonspecific but a gene probe lights up the tandem repeats)

{53755} myotonic dystrophy
{14485} myotonic dystrophy
{14488} myotonic dystrophy
{14491} myotonic dystrophy

      On muscle biopsy, the pathologist sees:

      • lots of ring fibers

      • lots of central nuclei

      • sarcoplasmic masses, without sarcomeres

      • nuclei in chains

      • type I fiber atrophy

      Myotonic dystrophy is an example of a gene whose bad alleles typically become worse and worse with each generation, through progressive amplification of CTG-repeats. This is "Sherman's paradox / genetic anticipation". (More about this under "Huntington's chorea".)

        Another locus exists that does not exhibit anticipation.

    Facioscapulohumeral dystrophy

      The disease is of varying expressivity, and not lethal. Patients' shoulders and upper arms waste away, beginning in their teens or twenties.

      Apparently an autosomal dominant syndrome, the genetics have proved remarkably elusive. One idea is that it is caused by one's particular nuclear envelope protein alleles not working well together (Brain 129: 996, 2006).

      Staining muscle with NADH reveals "moth-eaten" or "mottled" myofibers. Other changes are not usually striking.

{14515} facioscapulohumeral dystrophy, patient

    Limb-girdle dystrophies

      The hips and/or the shoulders are involved, and weakness leads to progressive disability sometime during adult life.

      Muscle biopsy often shows central nuclei, but there are no specific findings.

      * Most typically, the mutation is in calpain-3 ("LGMD 2A"; update Brain 128: 732, 2005), dysferlin ("LGMD 2B"; Neurology 56: 660 & 1472, 2001), or one of the sarcoglycans (alpha-sarcoglycan=adhalin Nat. Genet. 11: 257 & 1266, 1995; 3 others known, update Neurology 67: 167, 2006). or POMT1 ("LGMD 2K"; wide range depending on allele: Neurology 66: 1564, 2006). In the less-common dominant forms, genes include myotilin, lamin A/C (remember progeria?), caveolin-3, and even collagen VI (several eponymous phenotypes depending on the mutation; as you'd expect, double-jointedness is common; Neurology 58: 593, 2002; Neurology 59: 920, 2002);

      * Some caveolin-3 mutations produce the rare but picturesque "rippling muscle disease", with wiggly waves on percussion; Neurol. 57: 2273, 2001.

{14521} limb-girdle dystrophy, patient
{14385} limb-girdle dystrophy, histology

    Congenital muscular dystrophy:

      Weak from birth. Several biochemical problems (update Arch. Neuro. 61: 189, 2004). The deficiency is most often in merosin, a laminin-like protein; you can diagnose these on skin biopsy instead of going after muscle (Lancet 347: 582, 1996). Gene LAMA2 update Arch. Neuro. 62: 1582, 2005; Neurology 63: 1118, 2004.

      in "fiber type disproportion", type I fibers are much smaller than type 2 fibers. This is a feature of several known congenital myopathies, and others that are presently unclassified.

      Centronuclear myopathy with vacuoles
      Electron micrographs
      VCU Pathology

    Many other forms of muscular dystrophy exist (laminin deficiency: Neurology 55: 1120, 2000; lots more).

OTHER HEREDITARY MUSCLE DISEASES ("the other congenital myopathies"; floppy babies or lousy athletes)

    You have already studied the glycogen storage diseases. For review:

      Pompe's glycogenosis II (acid maltase deficiency / glucosidase) produces floppy babies, big hearts, and often early death from cardiac failure; milder forms exist.

{15334} teen with mild acid maltase deficiency; looks okay but tires easily at sports

      McArdle's glycogenosis V (myophosphorylase deficiency) is a mild disease. Glycogen bumps lie beneath the sarcolemma. Patients are poor athletes, and if they try or are forced, they get bad cramps and rhabdomyolysis. Genes: NEJM 329: 241, 1993.

        * The mainstay of therapy, such as it is, is an oral sucrose load before exercise (NEJM 349: 2503, 2003). Creatine therapy has had some success but too high a dose actually makes the disease worse (Arch. Neuro. 59: 97, 2002).

McArdle's
Pittsburgh Pathology Cases

McArdle's Disease
Pittsburgh Illustrated Case

McArdle's Glycogenosis
Brazil Pathology Cases
In Portuguese

    Mitochondrial myopathies are inborn errors of metabolism that seem to primarily involve mitochondria. They feature defects in the pyruvate dehydrogenase complex, tRNA synthetases (probably most common, for example Neurology 44: 975, 1994), ATPase production, and the cytochromes (mitochondrial or autosomal inheritance, see Neurol. 44: 721, 1994). Some also involve the brain ("encephalomyopathies").

      They include the mitochondrial-inherited Kearns-Sayre syndrome, with ophthalmoplegia, retinal pigmentation, cerebellar ataxia, and heart block. By now, dozens of distinct mitochondrially-inherited diseases affecting muscle are known, and drugs such as AZT and suramin produce acquired lesions that look similar.

AZT myopathy
Ragged red fibers
Great photo from NEJM

      The histologic hallmark of most of these illnesses is ragged red fibers. These are ragged because there are too many mitochondria, often abnormal ones, clustered around their edges under the sarcolemma. (* Future pathologists: See them best using Gomori trichrome stain.)

        * Pathologists today also stain for cytochrome oxidase; patchy areas with deficient staining strongly suggest mitochondrial myopathy. Review Am. J. Clin. Path. 116: 326, 2001.

        * The clever screening test is to have the patient squeeze the hand-gripper for three minutes; a very low pO2 in the venous blood from that arm indicates mitochondrial myopathy (Neurology 58: 1533, 2002).

      On electron microscopy, the damaged mitochondria contain "parking-lot crystals" of abnormal *  creatine kinase (Proc. Nat. Acad. Sci. 91: 5089, 1994).

{14435} mitochondrial myopathy; mitochondrial clusters are dark purple
{14436} mitochondrial myopathy; mitochondrial clusters are dark b;ie

Mitochondrial myopathy
Electron micrographs
VCU Pathology

      * A mitochondrial myopathy that'll look normal on biopsy is mutated cytochrome C disease (NEJM 341: 1077, 1999). These patients have severe exercise intolerance and are likely to have lactic acidosis even at rest.

      * Defects in carnitine metabolism include several obscure diseases (Pediatrics 84: 312, 1989; Am. J. Ob. Gyn. 170: 1390, 1994). Depending on the problem, muscle cells may be fat-laden or appear normal. There are no "ragged red fibers".

      * Hereditary coenzyme Q deficiency features ragged red fibers, and responds dramatically to generous doses of supplemental coenzyme Q: Neurology 57: 515, 2001.

    Rod myopathy ("rod body myopathy", "nemaline myopathy"; "nema"- means "thread") is a family of autosomal-dominant (usually), non- progressive (usually) disorders with widely variable penetrance. The "nemaline rods" are masses of Z-band material (* notably actinin, where the problem seems to be. Chemistry: J. Neurol. Sci. 93: 199, 1989.

      * Future pathologists: Gomori trichrome accentuates the red-purple staining. The "rods" are not exactly pathognomonic, but dominate the picture in this entity. See Hum. Path. 21: 77, 1990. One of the genes is tropomyosin 3, another is actin (Nat. Genet. 23: 208, 1999).

{14376} rod body ("nemaline") myopathy
{14378} rod body ("nemaline") myopathy
{14379} rod body ("nemaline") myopathy, Gomori trichrome stain

    * Lipid myopathy features fatty change as the major finding. Most of these people have a deficiency in carnitine palmitoyltransferase, and have weakness and rhabdomyolysis if they over-exercise (J. Neuro. Neurosurg. Psych. 62; 169, 1997.)

    * Central core disease is actually a group of variably-inherited, variably-severe, often non-progressive diseases that produce a great preponderance of type I fibers, many with a full-length "central core" where there are no organelles and even the sarcomeres may be scrambled. (Future pathologists: See it with the NADH tetrazolium reductase stain, or even PAS.) The most common gene is the ryanodine receptor, the intracellular calcium release channel (Neurology 59: 284, 2002; another allele and syndrome here Neurology 65: 1930, 2005).

    * Myotubular myopathies, variously inherited and variably severe, form another plethora of diseases. The deadly X-linked recessive form is caused by lack of good myotubularin, an ancient membrane protein (Nat. Genet. 18: 303, 1998, Nat. Genet. 13: 175, 1996.

    * Desmin myopathy (desmin gene mutated): NEJM 342: 770, 2000.

    * Spheroid body myopathy (mutated myotilin): Neurology 65: 1936, 2005.

    * Myofibrillar myopathies are genetic diseases with dissolution of the sarcomeres beginning at the Z-disk. Several are known (Neurology 62: 1363, 2004; Brain 127: 439, 2004).

{27319} central core disease; patient (no really diagnostic features visible)
{27331} central core disease; patient (no really diagnostic features visible)
{27352} central core disease; patient (no really diagnostic features visible)
{27325} central core disease, patient

    Inclusion body myositis (Am. J. Path. 156: 1835, 2000; Am. J. Path. 164: 1, 2004):

      A fairly common hereditary or sporadic inflammatory-necrotizing myopathy. The sporadic form is common in older adults; it involves especially the grip muscles.

      The histopathology is distinctive. There are vacuoles containing (surprise!) phosphorylated tau twisted as paired helical filaments, just like the tangles in Alzheimer's, along with some other Alzheimer proteins. There's also prion precursor protein and apoprotein E. It stains as amyloid.

      In fact, the biochemistry seems similar in many ways to the changes in Alzheimer's (Neurology 66(2 S 1): S-39, 2006), and it is being called a "myodegenerative disease".

      * It is basically not treatable, and is notoriously unresponsive to anti-inflammatory medicines. See Neurology 45: 1302, 1995.

      * The hereditary form results from lack of one of the carbohydrate-processing enzymes (Neurology 59: 451, 2002).

RHABDOMYOLYSIS

    Sometimes myoglobin leaks out of skeletal muscle. This may be acute or chronic.

      Some normal people get rhabdomyolysis after exercise. If you're out of shape and overdo it, you'll probably experience mild rhabdomyolysis (ouch!). If severe, you might have glycogen storage disease (V or VII), or some other unusual problem. We might hypothesize pH-related cell injury, but details are obscure.

      Other causes of rhabdomyolysis include crush injury, electrical injury, heat stroke, motor seizures, cocaine abuse, malignant hyperthermia (see below), neuroleptic malignant syndrome (from the strong dopamine D2-blocking anti-psychotic drugs), long-term glue sniffing (J. Tox. 38: 679, 2000), or acute systemic viral illness.

      Alcoholic rhabdomyolysis / myopathy is a minor mystery of medicine when it occurs apart from obvious trauma (Minn. Med. 71: 769, 1988). Some (but probably not all) of the explanation is that alcoholics (and dopesters) get ischemia of skeletal muscle by not shifting their weight (i.e., people who are passed out don't fidget, toss, and turn like we do.)

      Statin myopathy: JAMA 289: 1681, 2003.

    Markers for rhabdomyolysis are the same as for any other disease that releases the contents of myofibers. Myoglobin appears in the urine, and the "muscle enzymes" (creatine kinase, aldolase, SGOT, others) rise in the serum.

      Large amounts of myoglobin in the glomerular filtrate tend to precipitate in the kidney tubules. Pigment nephropathy is troublesome but seldom lethal.

    Regardless of cause, muscle biopsy in "rhabdomyolysis" shows degenerating and regenerating fibers, with macrophages around them, but no lymphocytes or other inflammatory cells.

    Lovastatin / niacin rhabdomyolysis
    Pittsburgh Pathology Cases

    This might be a good place to mention myositis ossificans, in which endochondral bone formation occurs within the muscular connective tissue.

      Localized myositis ossificans follows trauma and probably represents bony metaplasia of scar ("myositis ossificans traumatica"). Pathology of the developing lesions: Clin. Ortho. Rel. Res. 403-S: S-110, 2002.

      Progressive fibrodysplasia ossificans (formerly "generalized myositis ossificans") is a dreadful disease in which new cross-links form across the joints, rendering them immobile. These patients' skeletons end up in pathology museums.

        * The cause is some mutation that produces excessive production of bone morphogenetic protein 4 (NEJM 335: 555, 1996). The "noggin" gene as one locus: Am. J. Med. Genet. 102: 314, 2001.

{27349} myositis ossificans; bumps are bone

Myositis ossificans
Pittsburgh Pathology Cases

    On your surgical rotations, you'll learn about the various compartment syndromes, in which swelling (especially from reperfusion of muscle ischemic for some other reason) within one of the deep compartments of an extremity interferes with venous drainage and causes infarction.

      * Dystrophic calcification of dead muscle here simulates tumor: AJR 187: W67, 2006.

INVOLVEMENT OF MUSCLE IN SYSTEMIC DISEASE

Ipecac myopathy
Pittsburgh Pathology Cases

    Probably the most common myopathy you will see (and probably ignore) is alcoholic myopathy. Biopsy that scrawny drunkard's muscle, and you'll find fibrosis between the fibers, and hypertrophy of the remaining fibers (i.e., many fibers are long- gone). We now know that these are the pretty much the same patients that have the alcoholic cardiomyopathy (Ann. Int. Med. 120: 529, 1994).

    You are already familiar with the catastrophic clostridial infection gas gangrene, in which muscle is prominently involved.

    You are also familiar with trichinosis, in which worms encyst and die in the muscles (they seek the busiest and best-perfused, i.e., the diaphragm and external eye muscles).

    Lots of granulomas in the muscle probably indicates sarcoidosis. Twice I've picked up polyarteritis nodosa (surprise!) on muscle biopsy.

    The virus that attacks muscle most aggressively is probably coxsackie B virus; also remember dengue. Myositis contributes to the agony of typhus.

    "White muscle disease", from selenium deficiency, is mostly a veterinary problem, but is seen occasionally in malnourished people (Neuro. Neurosurg. Psych. 67: 829, 1999).

    You'll need to decide for yourself about "macrophagic myofasciitis", sheets of macrophages within skeletal muscle but without muscle damage; supposedly a persistent local reaction to aluminum adjuvants in vaccines (Med. J. Aust. 183: 145, 2005) though it also occurs where there has been no vaccination (Scand. J. Rheum. 34: 65, 2005); the anti-immunization community considers it to be the cause of chronic fatigue syndrome and multiple sclerosis (Brain 124: 974, 2001). By contrast, there is a hereditary illness in which these lesions are widespread and the macrophages are loaded with aluminum (Neuromusc. Dis. 14: 246, 2004).

{46215} pus in necrotic muscle infected with bacteria; this is unusual
{08215} trichinosis
{08288} trichinosis
{15750} trichinosis
{24498} trichinosis

Trichinosis

Yutaka Tsutsumi MD

    We hope you are already acquainted with the miserable polymyositis-dermatomyositis ("idiopathic inflammatory myositis", review Lancet 335 53, 2000). Worth reiterating:

      The problem seems to be that muscle cells start expressing MCH-I antigens, and T-cells then become angry with them.

      Selective atrophy of the muscle fibers at the edges of the fascicles is very characteristic, even if there is no inflammation or necrosis. In more severe cases, patches of chronic inflammation are typical, and you may see injured or dying fibers.

      HIV infection at any stage can simulate polymyositis (Arth. Rheum. 49: 172, 2003).

{29501} polymyositis, histology
{05780} polymyositis, histology
{09039} polymyositis, histology
{14352} polymyositis, histology
{14356} polymyositis, histology; obvious perifascicular atrophy
{14358} polymyositis, histology; obvious perifascicular atrophy
{14433} polymyositis, really bad inflammation
{29504} polymyositis, histology, showing regeneration

      The most characteristic autoantibodies are directed against several of t-RNA synthetases (J. Immunol. 144: 1737, 1990). Anti-Jo-1 (anti-histidyl-tRNA synthetase) was the first of these antibodies, which are considered markers for polymyositis & perhaps pulmonary fibrosis. However, these occur only in a minority of cases.

      In a large minority of cases, the disease is the first sign of an internal malignancy, especially ovarian cancer.

    HIV-associated lipodystrophy syndrome is a well-known problem faced by patients on long-term retroviral therapy. No one really knows how it happens. It features redistribution of bodyfat from the subcutaneous tissues into the skeletal muscles, development of insulin resistance, and very low levels of adiponectin (J. Clin. Endo. Metab. 88: 627, 2003). The mainstay of therapy is intensive exercise, both aerobic and resistance; metformin may be helpful.

POLYMYALGIA RHEUMATICA (Med. Clin. N.A. 81: 195, 1997; Lancet 350: 36, 1997)

    A poorly understood but important disease. Almost all patients are older adults, and the majority are women. Many, if not most, have temporal arteritis (if you ask and/or palpate). There is pain and morning-stiffness in the neck, shoulders, and hips. Physical exam and routine labs are singularly un-diagnostic. The pathology is really more in the synovium and bursa than in the muscles (Arth. Rheum. 44: 115, 2001). Erythrocyte sedimentation rate is often, but not always, high. The treatment is tiny doses of systemic glucocorticoids, and patients are grateful.

CRITICAL ILLNESS MYOPATHY ("acute quadriplegic myopathy" was the original name for the group of illnesses; there are now many other names, first major review; Crit. Care Med. 27: 2544, 1999; updates Muscle and Nerve 23: 1785, 2000; Muscle Nerve 32: 140, 2005); Chest 131: 1541, 2007

    Recently recognized as more-than-just-atrophy. It first came to be recognized when patients on systemic glucocorticoids for emphysema (yeah) or severe asthma or other illnesses would develop profound weakness and pain, of relatively abrupt onset (Am. J. Resp. Crit. Care Med. 153: 1958, 1996). Soon it was noted that administration of paralyzing agents to steroid-treated people already on the respirator seems to precipitate the disease (Am. J. Resp. Crit. Care Med. 153: 1686, 1996; Neurology 46: 600, 1996). It was noted that some these patients never got their strength back.

    * Medical terminology buffs: "critical illness" seems to be variably defined, but with some failure of multiple organs already evident and "systemic inflammatory response syndrome" presumably present (Muscle Nerve 2005 op cit blames the multiple lines and intubation in patients in the ICU for over a week).

    In the original biopsy studies of the entity we came to call "acute necrotizing myopathy of intensive care" (i.e., the one that doesn't get better), pathologists observed:

    • angulated, atrophic fibers;

    • basophilic regenerating fibers;

    • necrotic fibers

    • fibrosis between the fibers

    • the usual nonspecific stuff (more central nuclei, etc.)

    After much study, today's pathologists divide "myopathy of critical illness" into several subtypes, which may occur together.

    • thick-filament myopathy

    • "acute necrotizing myopathy of intensive care"

    • acute rhabdomyolysis

    • disuse ("cachectic") myopathy

    Probably these illnesses have always been with us, but we are only noticing them because of better survivals by victims of catastrophic illness. In fact, a large majority of patients in the ICU have some degree of myopathy if you do direct muscle stimulation (JNNP 77: 500, 2006); about half will also show the neuropathy.

    Thick filament myopathy is striking, both on H&E and on electron microscopy. Myosin, but not actin, disappears (Neurology 55: 854, 2000). The typical patient is an asthmatic who suddenly got much worse and had to be put in a ventilator. Patients usually got glucocorticoids and/or NJM blockers. Occasionally it follows sepsis. Most patients recover if the underlying illness is treated successfully.

    As you'd expect, acute necrotizing myopathy of intensive care features vacuolization, necrosis, and phagocytosis of muscle fibers. Expect weakness, very abnormal electromyography, a greatly elevated creatine kinase, and a poor outcome. Thankfully, it's rare.

    In acute rhabdomyolysis, the clinical picture will be similar to the acute necrotizing illness, but electromyography will be near-normal. Also uncommon, No one understands why it occurs in ICU patients at all; again, NMJ blockers and glucocorticoids seem to precipitate it.

    Disuse myopathy is simply the weakness that develops in unused muscles over time. Remember that type II fibers atrophy more than type I's.

    We will cover the better-understood critical illness polyneuropathy, another weakness syndrome that may well be present in these patients as well, when we talk about peripheral nerve disease. It evidently results from the systemic inflammatory response syndrome, familiar from general pathology.

    In the meantime, loss of movement in a comatose ICU patient may not mean deterioration in brain function (Lancet 347: 1579, 1996 pointed out the obvious). The question of whether muscle biopsy is indicated depends on the big picture.

Confusing: "Steroids" in the muscle literature as elsewhere means either glucocorticoids or androgens (see below).

Chloroquine is notorious for producing a myopathy with vacuoles in muscle cells (no marvel; chloroquine exerts its major effects on lysosomes).

THE MUSCLE MEMBRANE DISEASES: Electrical troubles! Old review: NEJM 328: 482, 1993. The chloride channel itself: Neurology 54: 937, 2000.

    Chloride channel disease -- Myotonia congenita: several inherited diseases with excessive muscle tone.

      Patients often have considerable muscle hypertrophy and strength, excelling at sports where strength is more important than speed; some (not all) forms eventually cause atrophy. The histology is usually normal or nearly so.

        * Goats with myotonia congenita are bred for thier superior meat.

{14500} myotonia congenita with hypertrophy
{14503} myotonia congenita, older patient with atrophy
{14506} myotonia congenita, older patient with atrophy

      The usual gene for both the common dominant (Thomsen's mild disease * Thomsen had it) and recessive (Becker's more serious disease, not to be confused with Becker's dystrophy) have been found at the CLC-1 ("chloride channel 1") locus on chromosome 7q (Science 257: 797, 1992).

      Stay tuned for the discovery of several more alleles here that determine why some guys "naturally" have much bigger muscles than other guys (i.e., it's not just your testosterone or your "bone structure", dudes).

      Myotonic dystrophy, of course, also features an electrical disturbance; the gene involves a membrane component.

    Periodic paralysis:

      Several hereditary (usually autosomal dominant) diseases, which feature striking episodes of paralysis without clouding of consciousness.

      Precipitated respectively with low, normal, and high serum potassium, all seem to respond to carbonic anhydrase inhibitors, and pathologists seldom see them. Probably some of them go into the SIDS "we don't know exactly why" category.

      Hyperkalemic periodic paralysis shares a locus with paramyotonia congenita (a cold-sensitive myotonia) and potassium-aggravated myotonia, at a sodium channel on chromosome 17q (SCN4A: J. Neurosci. 19: 4762, 1999). More mutations Neurology 44: 1500, 1994. Yet another allele: Arch. Neur. 51: 1095, 1994 ("myotonia fluctuans").

      Hypokalemic periodic paralysis type I is a dominant calcium channel mutation (Am. J. Hum. Genet. 56: 374, 1995). type II is a dominant sodium channel (CACNA1S: Brain 125: 835, 2002; Neurology 53: 1932, 1999; Neurology 57: 1323, 2001). There is also a dominant potassium channel (KCNE3) disease that expresses itself best in the presence of hyperthyrodism; don't ask why (J. Clin. Endo. Metab. 87: 4881, 2002).

      * Anderson's (periodic paralysis, sudden death) is a potassium channel (KCNJ2) mutation: Circulation 105: 2592, 2002.

    Malignant hyperthermia susceptibility

      Some people (around 1 in 5000), when they go under a general anesthetic, develop rhabdomyolysis, acidosis, elevated core temperature, and/or serious heart rhythm problems.

      The ability to get this is hereditary, usually autosomal dominant. The mutations are in the voltage-gated calcium channels in skeletal muscle; * the most common locus is RYR1, ryanodine receptor; Lancet 352: 1131, 1998; recessive Neurology 59: 284, 2002)

      * Update on how to screen: JAMA 293: 2918, 2005 (i.e., you really can't).

    Not skeletal muscle, but worth mentioning again: Sodium channel N5a mutation causes "Brugada's ventricular fibrillation" (Nature 392: 293, 1998). Stay tuned for more membrane-channel diseases (* for example, hereditary epilepsy from defective potassium channels: Nat. Genet. 18: 53, 1998).

OTHER MUSCLE PROBLEMS

    Myofascial pain syndromes (Arch. Phys. Med. Rehab. 83 (3S1): S40, 2002; Am. Fam. Phys. 65: 653, 2002) are presently a major mystery of medicine.

      Patients may appear to have some other neuromuscular disease, or to have fibromyalgia, or to be "crocks", but they have palpable tender nodules / "trigger points" within their muscles. You can feel a tautness in the muscle, which twitches on tweaking and grows sore (local / referred) on pressure.

      The problem is electrophysiological (Am. J. Phys. Med. 81: 212, 2002). The connection between these nodules, TMJ syndrome, fibromyalgia, interstitial cystitis, and so forth will be clarified someday. No one knows the anatomic pathology.

      Acupuncture fails totally: Arch. Phys. Med. Rehab. 82: 986, 2001; botox offers some hope Arch. Phys. Med. Rehab. 84 3S1: S69, 2003; electronic muscle stimulation helps Am. J. Phys. Med. Rehab. 76: 471, 1997.

    Eosinophilia-myalgia syndrome

      This was a myositis (etc., primarily a vasculitis, and with scleroderma-like skin changes), with severe pain and weakness, seen in people who took a certain brand of L-tryptophan tablets from the "health-food" industry. Circulating levels of eosinophils were very high, and eosinophils and their debris were abundant in the damaged tissues.

      The cause was the impurity 1,1'-ethylidenebis[tryptophan]. Review: Mayo Clin. Proc. 66: 535, 1991). See also South. Med. J. 83: 675, 1990; Chest 97: 1032, 1990; NEJM 322: 869, 1990; Hosp. Pract. 27(4A): 65, April 30, 1992.

        * The problem was that the bacteria that produced the tryptophan were genetically-engineered to make preposterously large amounts. Common sense would suggest there would be unwholesome by-products. Showa Denko, the Japenese chemical firm that had previously produced the world's second-largest outbreak of deaths from mercury pollution, didn't bother checking for or removing the impurities. For no reason except to appear politically correct, all tryptophan supplements were banned as a result, and the anti-biotechnology community has made tremendous political capital off the fiasco.

      * Don't worry about similar, rare diseases (eosinophilic fasciitis, the controversial "human adjuvant disease" following implants, etc.)

    Rhabdomyoma
    Pittsburgh Illustrated Case

    Rhabdomyosarcoma

{24748} rhabdomyosarcoma (striations)
{09006} alveolar rhabdomyosarcoma; very undifferentiated tumor
{25305} sarcoma botryoides with cambium layer

Alveolar Rhabdomyosarcoma
Tom Demark's Site

Rhabdomyosarcoma
WebPath Photo

Rhabdomyosarcoma
WebPath Photo

HERE'S A SELECTION OF MUSCLE PATHOLOGY


Action hero -- 1950's
Kirk Douglas as "Spartacus"

Action hero -- 1980's

ATHLETICS

Sports do not build character. They reveal it.

          -- Heywood Hale Broun, TV commentator

    Muscles are fun. Athletes push their bodies to extremes seldom seen even in disease.

      * At Northwestern, we had a histotechnologist who ran 16 miles to and from work daily. It was fun introducing him to clinicians and having them "check out his heart".

      The pediatric athlete: Orthop. Clin. N.A. 26: 453, 1995.

    Aerobic training ("getting in shape") involves repetitively forcing the muscle to maximum metabolic demands. Aerobic exercise: Science 276: 1325, 1997.

      You measure aerobic fitness by how much oxygen you can use, for your size, in a minute.

      Aerobic training changes a number of parameters. Perhaps the most important is an increased mitochondrial activity in both type I and type II fibers (Am J. Physio. 278:E-153, 2000). Glycolytic enzymes are increased, and there is also talk of increased numbers of capillaries.

      Unless the muscle is working against resistance, don't expect to see a significant gain in muscle mass or strength.

        The best-established finding in aerobically-trained muscle is the increase in lactate transporter on both mitochondria and sarcolemma; I hope this is not a surprise (Am. J. Phys. 278: E571, 2000; Eur. J. Appl. Phys. 96: 636, 2006). It's now clear that how much you can improve this by exercising is genetically determined (J. Clin. Endo. Metab. 92: 1927, 2007).

    Of course, the changes of the aerobically-trained person are not confined to voluntary muscles. The muscle that is most affected by aerobic training is the heart. It undergoes hypertrophy (which is good in this instance; it can also beat slower). Claims of "improved lung function" are hard to demonstrate, but the shapes of marathon runners' chests do change to improve air supply. Ask a trainer about carbohydrate-loading to increase muscle glycogen stores (and thereby endurance) before the big race.

    Being aerobically fit clearly is a powerful way of forestalling the onset of type II diabetes (Ann. Int. Med. 143: 251 & 323, 2005); the studies are getting more and more impressive.

    * How does exercise help your lipoproteins? This year, the explanation goes like so: (1) exercising muscle's lipoprotein lipase selectively removes triglyceride from VLDL's; (2) this shrinks them and cholesterol molecules fall off the surfaces; (3) and the cholesterol ends up on HDL.

    * Being fit helps older folks sleep better, etc., etc., etc., JAMA 277: 32, 1997.

    We're still reading studies that "show" the benefits of exercise to be tremendous (for example, JAMA 273: 1093, 1995 measured aerobic fitness and found an 8x reduction in coronary mortality, and an overall mortality reduction in 44%; similar Lancet 352: 759, 1998). Before you embark on your own aerobic fitness program, reflect that (1) being sick lowers your aerobic fitness, and (2) being sick in the first place makes it less likely that you will exercise, and (3) people who exercise have other healthier habits. Of course you cannot control for these in a prospective study.... The retrospective review in JAMA 276: 205, 1996 struck me as more credible, and the benefits are almost certainly real.

    NIH consensus statement about physical-fitness and cardiovascular health: Am. Fam. Phys. 54: 763, 1996, JAMA 276: 241, 1996. The Surgeon General: JAMA 276: 522, 1996.

    * Uncle Sam spends megabucks on "the primary prevention of heart disease" at the grammar school level, including extensive indoctrination of the kids, and ends up proclaiming triumphantly that kids in the study group (i.e., who'd been told at length what Uncle Sam wanted them to say) reported reducing their percentage of fat calories by a whopping 2%, and reported exercising 12 more minutes a day than controls. Uncle Sam also compared body size and cholesterol levels (no difference) but not adiposity or muscularity. JAMA 275: 768, 1996. Your tax dollars at work. More from Uncle Sam: He spent more money in 1996 and discovered that most fat people do not exercise much during their leisure time (JAMA 275: 905, 1996), wow. In 1998, more of your tax money went to show that kids who watch more TV exercise less and are fatter! The authors wanted more money so they could spend it on health promotion (JAMA 279: 938, 1998), uh huh.

Muscle strength training ("getting bulked up") involves overcoming resistance, typically "pumping iron".

    Muscle strength is proportionate to muscle mass. A large limb muscle can lift about 3 kg/cm2 of its maximum cross-sectional area. The amount of load that a muscle can hold steady is around 40% greater than the amount it can lift, and for very strong men, this exceeds the force holding the tendons to the bone. Ruptures of the biceps and other tendons are not uncommon.

    A person's muscle mass ("muscle bulk") is determined by a combination of heredity (* probably including differences in base muscle tone and the genetic markers listed below), personal average androgen levels (widely variable even among people of the same gender), and the strength demands placed on the muscle.

      By contrast, "muscle definition" ("getting trimmed / ripped / cut") results from both muscle bulk and (more important) lack of subcutaneous fat. Much sought-after, bodybuilders diet and do even aerobic exercise before shows or photos. It is probably not possible to "spot-reduce" fat from one portion of your body, and be skeptical when someone tells you a particular exercise is "particularly good for definition".

      As noted above, an aerobically-trained adult also has about one liter more blood, which helps a "cut" person look "vascular" too. Again, much sought-after (contrast anorectics and zero-bodyfat "heroin chic" addicts).

    As I predicted in 2001, the study of the serum autocrine factor "myostatin" has become central to the field of muscle physiology (Science 296:1486, 2004). The hormone enables fat production and muscle atrophy. Belgian Blue cattle, which are lean and grotesquely muscled, lack myostatin (Nat. Genet. 17: 71, 1997). So are knockout mice lacking this protein (Proc. Nat. Acad. Sci. 98: 9306, 2001), and there's now a homozygous baby (NEJM 350: 2682, 2004 -- Mom won't say who Dad is, but she and her family are strength athletes, surely heterozygotes).

      * There will eventually be biotech products for bodybuilders and for reversing cachexia. As I predicted, there are now a bunch of scams based on the above work.

    "Supraphysiological doses of testosterone" (NEJM 335: 1, 1996) and resistance training both (and especially together) cause hypertrophy of the fibers (type II fibers in every sport, type I's when endurance is a factor), with increases in the numbers of myofilaments and even sarcomeres.

      * Of course, it was Virchow who demonstrated that muscles grow by hypertrophy rather than by hyperplasia.

    We now know that, despite traditional teaching, a weight-lifter's muscle fibers may divide, or (more important) new fibers form from satellite cells. ("Muscles have a memory" after all. See Anat. Rec. 233: 178, 1992; Med. Sci. Sport 31: 1528, 1999.)

    The key to building bulk is (1) lifting heavy weights (today's trainers recommend 3 sets of 6-10 repetitions of your maximum weight, three times a week), and (2) anabolic steroids (your own male hormones, or see below.) A man who lifts weights several times a week is likely to increase his muscle mass by around 30% after eight weeks. This will impress his male buddies and perhaps even a few women.

      * A new study confirms my impression that men who work-out think and act about the same as ordinary guys. There is a subset that the authors suggest calling "muscle dysmorphia", the guy who works out compulsively, is heavily-muscled, but won't take his shirt off because he thinks people will say he's too small (Am. J. Psych. 157: 1291, 2000).

    Some men bulk up much more easily than others do. Gym types talk about "easy gainers" and "hard gainers". The genetics of this is just coming clear. One locus is the angiotensin-converting-enzyme gene (where the allele seems to determine how much muscle you build in response to strength training): Lancet 353: 541, 1999; J. Clin. Endo. Metab. 86: 2200, 2001). Watch for variations in the myogenic proteins (such as "herculin"/Myf6/MRF4) to explain differences from person to person. You can read on your own about changes in myosin heavy chain subtypes in resistance-trained muscle, and so forth.

    Far more men work out with weights today than in past decades. This is probably healthy, and it has also changed the image of what a fit man is expected to look like (Am. J. Psych. 162: 263, 2005). Compare yesterday's action-hero macho-man actors with today's gentle-ordinary-guy actors; the old pictures of Superman with the new ones; and even GI Joe's from the 1960's with today's models.

{18664} "pumped"

Johnny Weissmuller as Tarzan
BEFORE working out became popular
Weissmuller was also a real athlete.

Mel Gibson, ~ age 50
Cast as an ordinary guy, AFTER
working out became popular

Douglas Fairbanks
Cast as an action hero BEFORE
working out became popular

Bruce Willis
Cast as a psychologist AFTER
working out became popular

Eroll Flynn
Cast as an action hero BEFORE
working out became popular

Kirk Douglas
Cast as a an action hero BEFORE
working out became popular

      The traditional wisdom in "exercise and the heart" was to emphasize the health-benefits of aerobic training, and to dismiss the idea that strength training has benefits beyond sports. This all changed in the 1990's.

        The academicians finally got around to seeing whether having post-polio patients pump some light iron helped, and of course it did (Am. J. Phys. Med. Rehab. 75: 50, 1996).

        Strength training helps old folks walk farther (Ann. Int. Med. 124: 568, 1996), re-muscles the elderly so they can do more ("reversing sarcopenia", Geriatrics 51: 46, 1996), strengthens rheumatoid arthritis patients and causes them to report less pain and less fatigue (Arth. Rheum. 39: 415, 1996), reduces (!) osteoarthritis activity in the knee (Nsg. Res. 45: 68, 1996), lowers diastolic blood pressure in older folks (Arch. Int. Med. 165: 756, 2005), etc., etc. Even the fibromyalgia patients benefit significantly (Arth. Rheum. 47: 22, 2002).

        Reports on strength training and lipids are mixed, but in 2007, the American Heart Association gave a reasoned, very extensive endorsement to resistance training for people both with and without heart diseaes (Circulation 116: 572, 2007).

        What's more, resistance training bulks the heart (Cardiology 90: 145, 1998) as aerobic exercise does. This was so politically incorrect that at first all the big-hearted bodybuilders in the study were wrongly accused just on this evidence of taking anabolic steroids. Science is now winning out over politics, at least here.

      Lifting is safe, even for younger kids if you supervise them properly (Sports Med. 15: 389, 1993), the emphysema folks (it makes them feel better! Thorax 47: 70