Muscle Hypertrophy and Anabolic Agents I

Lecture 20

Muscle AnatomyMuscles 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

Muscle Anatomy (continued)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.

Type I Fibers

Type IIb Fibers

Mitochondria

Fatdroplet

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).

Muscle Anatomy and TrainingWhat 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.

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.

Muscle Anatomy and Training

Muscle HypertrophyHypertrophy: 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)?

HYPERTROPHY HYPERPLASIAVS.

Hyperplasia?

Muscle HypertrophyHypertrophy: 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.

Satellite Cell Repair

Hawke et al. 2001

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.

Muscle Hypertrophy

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 themuscle cell

Muscle Hypertrophy and StrengthForce 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.

strength

cross-sectional area

X

Metabolic “cost” of muscleBesides 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.

Muscle Building NutritionTo 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)

The million dollar question…How to minimize the fat gain while maximizing muscle gain?

1. Maintain energy balance in state sufficient togain 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)

ANABOLIC STEROIDS

“STEROIDS FOR SALE!”

Steroid HormonesSteroids 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.

Ganong, 1995

TestosteroneTestosterone 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.

Athletes and AndrogensAthletes 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)

Testosterone

DHT Estradiol

(5-alpha reductase) (aromatase)

Responsible for male secondary sex characteristics

3 times as androgenic as testosterone, yet only 50% as anabolic

Responsible for female secondary sex characteristics

Ganong, 1995

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

Muscle Quality?

AAS and HIV

Orals vs InjectablesThere 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.

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.

WELL, IF WE PUT MORE BUILDING BLOCKS IN, MAYBE WE WILL MAKE MORE

“NATURAL” TESTOSTERONE...

ProhormonesProhormones 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?

OH

O

Testosterone

OH

O

Testosterone

IOC BANNED SUBSTANCES

STIMULANTSNARCOTICSDIURETICS etcPEPTIDE HORMONES

» HCG; LH; HGH; ACTH; IGF-1

ANABOLIC AGENTS» DHT; ANDRO; DHEA; TESTOSTERONE ETC» TESTOSTERONE/EPITESTOSTERONE > 6:1

Studies from Doug Kings lab at Iowa State show that:

1. 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

DO PRO-HORMONE SUPPLEMENTS WORK?

andro/DHEA » No serum T» estrogens » good cholesterol» No from trained/no supp

From bodybuildingforyou.com:

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

REAL WORLD VS RESEARCH

Cessation of Steroid UseIn 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

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

Androgen useestrogen