Muscle Hypertrophy and Anabolic Agents I

1. Muscle Hypertrophy and Anabolic Agents I Lecture 20

2. Muscle Anatomy • Muscles are made up of • bundles of individual fibers. • Each fiber is a single • elongated cell with a • nucleus, mitochondria, • endoplasmic reticulum, etc. • Muscle cells are subdivided • into myofibils composed of • actin and myosin filaments • linked in series in units • called sarcomeres. • Stimulus by motor neuron • causes actin and myosin to • interact; sarcomeres shorten • and produce force

3. Muscle Anatomy (continued) Fat droplet • 3 main types of muscle fibers • Type I: slow contraction, small, low • glycogen and CP, many fat droplets • and mitochondria, fatigue-resistant. • Type IIa: fast, intermediate size, high • glycogen and CP, pretty rich in • mitochondria, less fatigue-resistant • Type IIb: fast, large, high in glycogen • and CP, few mitochondria, not • fatigue-resistant. Mitochondria Type I Fibers Type IIb Fibers

4. All muscles • contain a mix of • fiber types. • Muscles that show • large gains in size • with training • usually have a • fairly high % of • Type-II fibers (e.g. • gastrocnemius vs. • soleus).

5. Muscle Anatomy and Training • What are the stimuli for hypertrophy? • 1. nutritional (energy balance, protein) • 2. hormonal (testosterone, insulin, growth hormone) • 3. stress (active training, passive stretch) • Most “trainable” fibers are Type-IIa. • After training they take on • characteristics more like Type I or Type • IIb depending on type of training.

6. Muscle Anatomy and Training • Fibers most sensitive to hypertrophy are Type-IIb. • This explains why muscle hypertrophy occurs in • response to stress of high force (resistance • training). These fibers are only used when rate of • force production is high. • There is huge individual variation in hypertrophy • response to training.

7. Muscle Hypertrophy • Hypertrophy: increasing muscle size. Hypertrophy • refers to increase in both the cross-sectional area of • the muscle (more myofibrils) and increase in length • of the muscle (more sarcomeres per myofibril). • Does the number of muscle fibers increase • (hyperplasia)?

8. Hyperplasia? HYPERTROPHY HYPERPLASIA VS.

9. Muscle Hypertrophy • Hypertrophy: increasing muscle size. Hypertrophy • refers to increase in both the cross-sectional area of • the muscle (more myofibrils) and increase in length • of the muscle (more sarcomeres per myofibril). • Does the number of muscle fibers increase • (hyperplasia)? Yes in some animals (e.g. cats) but • this does not seem to be a mechanism of hypertrophy • (ADULT) humans.

10. Satellite Cell Repair Hawke et al. 2001

11. Muscle Hypertrophy • Fibers do split as they get larger to maintain a • minimal surface area to volume ratio. • This splitting is beneficial because if volume • increases more than surface area diffusion • distance will increase and access to oxygen and • other compounds might be limited. • Splitting is not considered hyperplasia • because the fiber shares nuclei.

12. The combined • effects of nutrients, • hormonal environment • and mechanical load • (training) are • manifested by • changes in both gene • transcription and • mRNA translation to • increase myofibrillar • protein content in the • muscle cell

13. strength cross-sectional area Muscle Hypertrophy and Strength • Force generating capacity in muscles depends on • cross-sectional area. As area increases so does • capacity to generate force (strength). • Relationship is not 1:1 however. • Strength increases at a faster • rate than area (e.g. a 10% • increase in area results in a • 30% increase in strength). • This, in reverse, is a major problem in the elderly. • They lose muscle mass and small decline in muscle • size = big decline in strength. X

14. Metabolic “cost” of muscle • Besides obvious advantages of having more muscle • mass in terms of strength - larger muscle mass • helps with weight management. • Muscle tissue consumes a lot of energy (high • maintenance) and basal metabolic rate (energy • required for basic life function) is directly • proportional to muscle mass. • More muscle mass = higher basal metabolic rate = • more energy expended per day = require more • energy to maintain the same weight.

15. Muscle Building Nutrition • To gain muscle tissue it is necessary to create an • “anabolic” environment. Nutritionally, creating that • anabolic environment requires positive energy • balance (more energy in than out). • How much more energy in than out? This is the $$ • question b/c energy surplus also increases body fat • Competitive (natural) body builders know this and • incorporate 2 general phases: • 1. gain muscle and some fat (minimal if possible) • 2. lose fat and some muscle (minimal if possible)

16. The million dollar question… • How to minimize the fat gain while • maximizing muscle gain? • Maintain energy balance in state sufficient to • gain muscle while minimizing fat gain • 2. Hard resistance training • 3. Incorporation of cardiovascular training into routine • 4. Manipulation of the hormonal environment • (nutritionally and pharmacologically)

17. ANABOLIC STEROIDS

18. “STEROIDS FOR SALE!”

19. Steroid Hormones • Steroids are a group of • chemical messengers • that are synthesized • from cholesterol. Since • steroids are fat soluble, • they are membrane • permeable and often act • directly on the nucleus • of the cell. As you can • see by the structures to • the right, many of the • sex hormones have • similar structures.

20. Ganong, 1995

21. Testosterone • Testosterone contributes to male • sex characteristics including • muscle growth. Most testosterone • is produced in the testes (~95%); • remainder is produced by the • adrenal glands. Testosterone • has both anabolic (muscle building) effects as well as • androgenic (masculinizing) effects. Anabolic steroids mimic the actions of testosterone. Anabolic steroids are used medically to treat male patients with low levels of testosterone as well as muscle-wasting diseases. First used during WWII to help malnourished POW’s regain weight and strength.

22. Athletes and Androgens • Athletes have used anabolic agents to enhance • performance for 50 years. The goal is to maximize • anabolic actions (incr. strength and muscle mass) • while minimizing androgenic effects. • Testosterone is classified as a drug and requires a • prescription to obtain. It must be injected for • maximal effect. Banned by • most athletic bodies • (USOC, NCAA, etc)

23. (5-alpha reductase) (aromatase) DHTEstradiol Responsible for male secondary sex characteristics 3 times as androgenic as testosterone, yet only 50% as anabolic Responsible for female secondary sex characteristics Testosterone

24. Ganong, 1995

25. Are steroids effective? • Bhasin et al. “Effects of a supraphysiological dose of • testosterone on muscle size and strength in healthy • men”. NEJM 1996. • • 600mg testosterone enanthate given for 10 weeks • • Weight-trained drug group; gain in LBM of 13.6 lbs • • Untrained drug group; gain in LBM of 6 lbs • • Considerable strength gains reported from both • trained and untrained drug groups • • No noticeable side effects reported by subjects. • HOWEVER, this tells us nothing about the long term • effects. Anabolic steroids reduce HDL, increase LDL

26. Muscle Quality?

27. AAS and HIV

28. Orals vs Injectables • There are two types of anabolic steroids – orals and • injectables. Besides the obvious differences in • delivery method, orals have much shorter half-lives • than injectables. The half-life of most orals is 3-5 • hours. The main consequences of the short half-life • is that (a) they must be taken much more frequently • than injectables (b) they are designed to withstand • the digestive system as well as a trip through the • liver and thus must be taken in larger doses than • injectables.

29. Often oral steroids are methylated to decrease • degradation as they pass through the liver. • As a consequence, such drugs alter liver • enzyme levels and can cause hepatoxicity. • Methylation may also increase aromatization to • estrogen. • Injectables tend to have longer half-lives • (increased serum testosterone levels may • last up to 14 days). For this reason athletes • tend not to take injectable steroids before • competition because they are easy to detect.

30. WELL, IF WE PUT MORE BUILDING BLOCKS IN, MAYBE WE WILL MAKE MORE “NATURAL” TESTOSTERONE...

31. Prohormones • Prohormones are marketed to provide a “raw • material” that the bodies own metabolic machinery • can convert to testosterone. • Are “prohormones” • safer? If so, are • they effective?

32. OH Testosterone O

33. OH Testosterone O

34. IOC BANNED SUBSTANCES • STIMULANTS • NARCOTICS • DIURETICS etc • PEPTIDE HORMONES • HCG; LH; HGH; ACTH; IGF-1 • ANABOLIC AGENTS • DHT; ANDRO; DHEA; TESTOSTERONE ETC • TESTOSTERONE/EPITESTOSTERONE > 6:1

35. Studies from Doug Kings lab at Iowa State show that: • DHEA does not increase testosterone or strength • compared with placebo (but no increase in estrogen) • 2. Androstenedione does increase testosterone but • also increases estradiol. No impact on strength • compared with placebo. • BUT: this study was criticized b/c subjects were not • weight trained. Other studies done after this one • suggest that androstenedione supplementation DOES • raise testosterone levels and increase gain of muscle • mass relative to placebo

36. DO PRO-HORMONE SUPPLEMENTS WORK? •  andro/DHEA • No  serum T •  estrogens •  good cholesterol • No  from trained/no supp

37. From bodybuildingforyou.com:

38. REAL WORLD VS RESEARCH Serving Size: 1 packet Servings Per Box: 30Whole Pituitary: 100mg Lyophilized Pineal: 250mcgHypothalmus: 100mg Orchic Powder: 100mgL-Glutamine: 150mg L-Tyrosine: 100mgL-Lysine: 100mg L-Arginine: 100mgL-Ornithine: 100mg Glycine: 600mg4-Androstenediol: 25mg 5-Androstenediol: 25mgNor-4-AndroDione: 25mg Nor-4-AndroDiol: 25mg

39. Cessation of Steroid Use • In order to understand the physiological • consequences of stopping steroid use here is a brief • review of the Hypothalamic-Pituitary-Testicular Axis • (HPTA) • hypothalamus  GnRH •  • anterior pituitary  LH and FSH •  • testes •  • testosterone

40. Cessation of Steroid Use (cont’d) • When using anabolic agents, high androgen levels exert • negative feedback on the hypothalamus and decrease the rate • at which GnRH is produced. The lower GnRH levels reduce the • amount of endogenous testosterone produced and if steroid • use stops it takes a while for the body to reequilibrate its own • testosterone production. • hypothalamus  GnRH •  • anterior pituitary  LH and FSH •  • testes •  • testosterone inhibition inhibition estrogen Androgen use