Role of Physical Activity and Exercise in Progressive Neuromuscular Disease

[Guest guest]

NIDRR Rehabilitation Research and Training Center in

Neuromuscular Diseases Roundtable Conference 2001:

Role of Physical Activity and Exercise Training in Progressive

Neuromuscular Diseases Sept. 30, Oct. 1-3, 2001 San Diego, CA

http://www.nmdinfo.net/lectures/mcdonald/mcdonald1/mcdonald1.html

CRAIG M. MCDONALD, MD

Assoc. Professor

Departments of PM & R and Pediatrics

UC School of Medicine

Director: RRTC in Neuromuscular Diseases; UCDMC Neuromuscular Disease

Clinic; UCDMC Pediatric Rehabilitation Program

Physical Activity in Neuromuscular Diseases

First of all, I would like to acknowledge Bill Fowler who I think is

the energy and driving force behind this whole state of the science

round table, and I think Bill deserves a big round of applause. He

has really put together a great program and I think you will all

enjoy it over the next few days.

This morning I am going to discuss issues pertaining to physical

activity as opposed to formal exercise protocols in neuromuscular

disease.

As Bill mentioned earlier, neuromuscular diseases are peripheral

disorders of the nervous system affecting anterior horn cells,

peripheral nerves, neuromuscular junctions and muscle. Really one of

the big challenges that we all have here in this room as we look at

this body of literature, is that with these neuromuscular disease, we

are dealing with well over 300 hundred diseases here, over 250

distinct genes have been identified which lead to the neuromuscular

diseases. Many of these are a very rare phenomenon, so when we are

talking about specific exercise guidelines, we have distinct

challenges in that many of the guidelines really need to be disease

specific, however, I think we owe it to our patients to come up with,

in additional, generalizeable guidelines which may be applicable to

the vast majority of patients. When we look at all these

neuromuscular diseases as a whole, the prevalence is really quite

substantial, 400,000, but when you look at acquiring additional

hereditary neuromuscular diseases, the overall prevalence when

looking at acquired peripheral neuropathy and so forth, over 4

million individuals are affected by neuromuscular diseases in the

United States. So really, a substantial number of individuals in the

United States are affected by these conditions.

Our Rehabilitation Research and Training Center has now been in

existence for 18 years, the current grant cycle or five year grant

cycle, we are in our third year now and focusing on enhancing quality

of life with persons with neuromuscular disease.

Ted Abresch spearheaded this project working with quality of life

according to consumers with neuromuscular diseases. Ted carried out

a comprehensive quality of life survey of 1,200 individuals with

neuromuscular diseases. These are the most frequent problems noted

by them that negatively impact their quality of life:

1. Weakness

2. Difficulty getting exercise

3. Fatigue/poor endurance

4. Problems with weight

I think all of these problems, the most important problems negatively

impacting quality of life are directly related to issues pertaining

to physical activity and exercise. So, this is really an important

issue.

Ted did administer the SF-36 in 1,200 individuals with neuromuscular

disease. To the question, how much does your health limit you from

the activities? Vigorous activities such as running, 93% were

limited by a lot; walking more than a mile, 84% had a lot of

limitation; walking several blocks 73% answered the question in this

regard. So, again, you can see that physical activity and exercise

is really a substantial issue for these consumers of neuromuscular

diseases.

This morning, I am going to focus on the impact of reduced physical

activity on health and fitness, methodologic issues relating to the

assessment of physical activity in the community and finally using a

prototype neuromuscular disease, I am going to discuss some

determinants of physical activity in a specific neuromuscular disease

population, Duchenne's muscular dystrophy.

The goals of physical activity and exercise in neuromuscular disease

historically increase in cardiopulmonary endurance, increase lean

mass, decrease fat mass, increase muscle strength and endurance,

improves flexibility, improves health outcomes such as coronary

artery disease, type II diabetes, and finally psychosocial benefits

have been noted in exercise and physical activity. These are well-

documented benefits in the able-bodies population, prevention and

control of coronary artery disease, hypertension, non-insulin-

dependent diabetes, osteoporosis, obesity, and a variety of

psychosocial mental health benefits as well with exercise. Persons

with neuromuscular disease represent a very sedentary deconditioned

population. They have lower work capacity, lower peak VO2 capacity,

reduced resting energy expenditure, probably on the basis of reduced

metabolically active lean tissue. There are body composition

changes, reduced lean muscle mass, increase in fat mass, particularly

in dystrophic neuropathy where muscles are replaced by fat and

connective tissue and then finally decreased muscle strength and

endurance.

Dr. mentioned a variety of age-related issues. In fact, in

sedentary subjects, sedentary able-bodied subjects, there are

definite specific age-related changes: Greater age-related decline

in VO2 max is noted in sedentary subjects; greater decrease in age-

related loss of muscle mass, called sarcopenia; greater loss in

sedentary subjects; greater increase in body fat, again in sedentary

subjects; greater decrease in strength and greater reduction in

walking speed has been noted in elderly populations with weak knee

extension.

The reviewed neuromuscular disease population does not only have

these disuse effects on the muscle, but there are also disease

effects. The disease effects may be the primary culprit in reducing

physical activity, reduced function of muscle mass as seen in the

disease. The individual then experiences reduced physical activity,

but then as a result of that reduced physical activity, there may in

turn be additional disuse atrophy and from that reduction in

functional muscle mass. So, as you can see, there may be a central

problem going on here, both with disease effects as well as with

disuse effects. Neufer stated, " To the extent that reduced exercise

performance is due to the effects of detraining from a sedentary

existence, endurance exercise may be helpful in reversing the

negative effects of the deconditioned state. "

Let me just briefly outline some of the current methods available to

us to objectively assess physical activity in the community.

Traditionally, many studies have used self-reported methods with

physical activity diaries. These have been are problematic,

particularly in younger populations, but our ability to recall our

physical activity, even over relatively short periods of time is

really fraught with a great deal of error. Doubly labeled water

techniques assess total energy expenditure, but really do not give us

information about the duration of physical activity, the intensity of

physical activity and time spent in various intensities of physical

activities. They really do not provide us with any profile of

physical activity. Standard pedometry has been problematic with

regard to accuracy but again usually gives us a total step count as

opposed to a minute-to-minute physical activity value. Various

accelerometers will be used, tri-axel accelerometers which assess

physical activity. Part of the problem with these is that passive

movement of the individuals, for instance, the individual gets into

an automobile or rides a bicycle, the accelerometer can register

three-dimensional acceleration with the individual exerting minimal

energy. Long-term heart rate monitoring has been used by Dr. Kilmer,

Sue Aitkens and other investigators at UC to assess

quantitative physical activity in the community.

I would like to outline a number of goals for any quantitative

assessment of physical activity. First, we would like to know when

during the day is the subject active versus sedentary. What is the

magnitude of peak activity? What is the average total daily physical

activity over an extended sampling time? Days to weeks rather than

just hours. What is the mean proportion time spent at defined

physical activity intensities? And finally, we would like a

monitoring system to be objective and unobtrusive so that it can be

utilized in the community setting and real world setting.

Most of you are familiar with heart rate monitoring. Continuous

heart rate monitoring is a form of activity assessment. The heart

rate is calibrated to oxygen uptake in the laboratory and then an

individual wears a heart rate monitor for a number of days. For this

regression, a VO2 heart rate regression is formulated and minute-to-

minute oxygen uptake is predicted from a minute-to-minute heart rate

based on a regression equation.

McCrory and Dr. Kilmer from our Research and Training Center at

UC did one of the first studies that had quantitatively

assessed physical activity in the neuromuscular disease

populations. They looked 26 adults with slow, progressive

neuromuscular diseases, myotonic dystrophy, hereditary motor sensory

neuropathy, Limb-Girdle dystrophy, FSH, Becker muscular dystrophy and

…………… disease, a motor neuron disease, spinal muscular atrophy type

III, so you can see, very heterogeneous population of slowly

progressive neuromuscular disease subjects that utilize community

heart rate monitoring and they estimated the activity associated

total energy expenditure as the difference between total energy

expenditure and the resting energy expenditure.

What they found really was quite striking in the male subjects, the

male neuromuscular disease subjects spent a reduced percentage of

their total energy expenditure engaged in physical activity minutes

active the 126 minutes per day versus 248 minutes per day in the

control subjects and again, the difference are even more dramatic in

the female subjects. A total of 29% of energy expenditure in

physical activity versus 44% and minutes active, 74 minutes active in

the female NMD subjects versus 206 minutes in the control subjects.

In this study, the NMD subjects reported spending less time

exercising, formally exercising than controls and when they did

exercise, the exercise was at a light level, controls exercised to

the moderate level. Body fat in these NMD subjects was inversely

related to minutes active and fat free mass.

More recently, we utilized an accelerometer system referred to as the

Step Activity Monitor, which gives us a minute-to-minute quantitative

value of physical activity in the real work environment. This

monitor is actually about the size of a digital pager. It is worn on

the ankle. The information collected over periods of up to 3-4 weeks

can then be downloaded into a laptop computer for analysis of minute-

to-minute physical activity in a quantitative sense. The accuracy of

the Step Activity Monitor has been established, this is observer

counted steps versus Step Activity Monitor reported steps, a very

close association there of greater than .99. Again, we get this type

of data on each individual subject. This would be a daily printout

of total steps per day, over 8,000; period spent jogging, walking to

the bus, walking to work, period spent in office work. So, we get

minute-to-minute step counts. Essentially, analogous to a Holter

monitor of ambulatory function. Again, desk work, very sedentary,

errands later in the day, walking home, doing some housework later in

the day. Again, a quantitative profile of minute-to-minute physical

activity. Not only that, but with the Step Activity Monitor, we can

actually calculate the minutes per day spent at a low activity level,

a moderate activity level and a high activity level. Again, we need

quantitative data regarding minutes spent at various activity

levels. We have done some normative studies in able-bodied

children. There is a gender affect in physical activity, which is

consistent with other physical activity assessment techniques done

with water and so forth. Males are more physically active than

females at a given age, and there is also, in addition to a gender

affect, there is an age-related affect. Younger than age ten,

decreasing activity with age to 16-20 years of age when children

reach more of an adult physical activity level in the community.

This is data on total daily steps per day.

Again, even looking at children with obesity, we can pick up subtle

differences in physical activity. This is data on children ages 6-

10. Minutes per day spent at a high activity level in obese

children, 50 versus nearly 70 in the non-obese children; fewer number

of steps taken at the high intensity activity and then we look at

data on total steps per day; the obese children 5,100 total steps per

day versus the control children who took 6,300 steps per day.

I would like change focus now and discuss some determinants of

physical activity and I think it is useful to utilize the model,

which was put forth by the National Center of Medical Rehabilitation

Research, which looked at specific domains of science relevant to

medical rehabilitation. Pathophysiology, impairment, functional

limitation, disability and societal limitation.

To illustrate how this framework can be useful, I would like to focus

now on Duchenne Muscular Dystrophy as a prototype of neuromuscular

disease. There is a very stereotypic pattern of progression in

Duchenne Muscular Dystrophy to a period of time when they lose

ambulation between the ages of 7-13, a mean wheelchair reliance age

of 10. Again the NCMRR model defined pathophysiology as interruption

of or interference with normal physiologic and developmental

processes or structures. The example here, pathophysiology: absence

of dystrophin leads to progressive loss of functional muscle fibers

in Duchenne Muscular Dystrophy. The gene, XP 21 locus, is the

largest gene that has been identified in the human genome, 2.4

million base pairs. This codes for the protein dystrophin, which you

are familiar with, a rod-shaped helical protein located on the

intracellular side of the sarcolemmal membrane and the protein in

turn bridges on to a number of transmembrane glycoproteins, the

sacroglycan complex and dystroglycans, which in turn bind on to

laminin in the extracellular matrix. So it appears that dystrophin

plans an important role in maintaining structural integrity of the

sarcolemmal membrane. This is an immunofluorescent stain of

dystrophin located just underneath the sarcolemmal membrane and a

muscle biopsy specimen.

Again, with regard to the pathophysiology of Duchenne Muscular

Dystrophy, we have a gene abnormality at the XP21 locus, usually a

deletion which leads to absence of dystrophin, susceptibility of

sarcolemmal membrane to mechanical injury, muscle fiber injury,

degeneration and then the muscle fiber goes through cycles of

degeneration and regeneration and eventually we have irreversible

cell death and replacement of that muscle fiber by fat and connective

tissue. Now, there is really a quite classic histology noted in

Duchenne Muscular Dystrophy. We see normal fibers, hypertrophied

fibers, degenerated fibers, atrophic fibers, regenerated fibers and

the hallmark of a great deal of connective tissue and fatty

infiltration.

Here is a normal ………stain of a muscle biopsy specimen of a three-year

old, nice orthogonal shape to the muscle fibers, peripherally located

nuclei with very little connective tissue. This is a muscle biopsy

specimen of a three-year old with Duchenne Muscular Dystrophy.

Again, you can see some hypertrophied fibers, some atrophic or

dystrophic fibers, some fibers with central nuclei, which are

regenerating and then again some connective tissue infiltration as

well as some fatty infiltration, already occurring in this three-year

old child with Duchenne Muscular Dystrophy.

This is an eight-year old child with Duchenne Muscular Dystrophy.

Again, not much muscle fiber left actually some hypertrophied fibers,

some fibers with central nuclei which are regenerating, some very

dystrophic, atrophic fibers with a tremendous amount of connective

tissue infiltration, some inflammatory cells and a great deal of

fatty infiltration at age eight.

This is a post-mortem specimen of a 19-year-old with Duchenne

Muscular Dystrophy. There just is not much muscle fiber left. You

have a few fibers, and the rest being really just fat. This is

actually a post-mortem photograph demonstrating the elbow, biceps

muscle, a great deal of subcutaneous tissue and the muscle just looks

yellow and fatty replaced. This is a picture of that individual's

gastrocnemius muscle. So again, there just isn't much muscle fiber

left in this 19-year-old individual post-mortem.

We can actually measure this fatty tissue replacement and degree of

lean tissue mass now with better body composition measures which

actually give us segmental body composition with DEXA (dual energy x-

ray absorptiometry). This is validated by pig carcass analysis.

Test-retest reliability is really quite high. More importantly, we

are actually able to get segmental body composition. There is an end-

stage DEXA scan in a 17-year-old male with Duchenne Muscular

Dystrophy. You can see the tremendous contractures this individual

has of scoliosis and again, this individual, you can't read it there,

but actually the DEXA scan shows the body weight. This 17-year-old

individual, has a body weight of 59 pounds. The percent of body fat

in this individual is 30% body fat with a total body weight of only

59 pounds. Again, there is not much functional muscle fiber left.

Greg : Can you get bone density off that?

Craig Mc: Yes

Greg : What's that bone density like?

Craig Mc: The bone density is usually quite diminished, bone

marrow content as well as bone density.

Greg : Do you know how early that starts?

Craig Mc: Actually, you can see that in the late school-aged

child of actually diminished bone density in Duchenne Dystrophy.

Body composition in Duchenne Dystrophy, again, in a series of

patients we studied, between the ages of 6-12, they had elevated

levels of total percent fat on DEXA and reduced total lean tissue on

the DEXA scans. What is interesting about Duchenne Dystrophy is that

we see a regional variation in body composition. Here is a DEXA scan

looking at thigh lean tissue versus upper arm lean tissue. Again,

there is really no substantial disability difference in upper arm

lean tissue, but there is a substantial decrease in thigh lean

tissue. Again, in the clinical findings of Duchenne Dystrophy in the

lower extremity weakness tends to predate the upper extremity

weakness, and perhaps the lower extremity fibers are experiencing

mechanical load or mechanic stress early on in the course of the

disease. There is a correlation again between body fat and physical

activity in Duchenne Dystrophy. Percent body fat by DEXA and total

steps per day was actually negative, correlating with a fairly high

correlation of –0.61.

Impairment- The NCMRR model defines impairment as the loss or

abnormality of cognitive, emotional, physiological or anatomic

structure or function, including all losses or abnormalities, not

just those attributable to the initial pathophysiology. The example

given in Duchenne Dystrophy, decreased strength in Duchenne Dystrophy

due to loss of muscle fibers, impaired contractility of muscle fibers

and/or disuse weakness of muscle groups would all be examples of

impairment of Duchenne Muscular Dystrophy.

We have done extensive quantitative testing in Duchenne Dystrophy

with isokinetic testing paradigms as well as isometric testing

paradigms. Here is actually some quantitative strength testing

values with age in Duchenne Dystrophy. At age six, actually their

quantitative strength on the dotted line as a percent of control

value shown over here. Their strength is only 50% of control value by

age six. So, relatively early in the disease process, their strength

is already 50% reduced and then it goes down from there.

This is manual muscle testing data, again showing the relative

increase in sensitivity of quantitative strength testing versus

manual muscle testing in individuals with weakness.

Now, we are actually able to normalize our quantitative of strength

measures to lean tissue measured by DEXA segmentally. We can

actually calculate the strength of the knee extensors per gram of

thigh tissue measured by DEXA. We can measure the strength of the

elbow flexors per gram of upper arm lean tissue as measured by DEXA.

We can see in a young population of six-year olds a dramatic

difference between Duchenne strength per lean tissue and control

strength per lean tissue. So, probably a better way to actually

evaluate quantitative strength testing data.

Again, impairment, on the NCMRR model is actually predictive of

functional limitation. There is a correlation between knee extension

strength and walking speed, which would be a functional limitation in

Duchenne Dystrophy that would be high, about .7, and again, study

that I published back in 1995, walking speed is actually very

predictive of time to wheelchair. We actually used that information

in the clinic to provide families with the anticipatory guidance as

to when they might expect their child to transition to the

wheelchair. Again, it goes both directions. Functional limitation

can, in turn, lead to further impairment. Examples of this in

Duchenne Dystrophy is transitioned to a more sedentary existence in a

wheelchair actually leads to an increase in contractures in Duchenne

Muscular Dystrophy. Also, short periods of bed rest, Dr.

mentioned the cast immobilization that his sister experienced. Short

periods of bed rest or immobilization results in significant loss of

strength and function in Duchenne Muscular Dystrophy.

Here is our natural history data on contractures in Duchenne

Dystrophy. This shows the key percentage of patients who develop

ankle plantar flexion contractures. Later in the course of the

disease, maybe 100% may have ankle plantar flexion contractures.

However, the contractures do not develop until after the child has

transitioned to the wheelchair, for the most part. There is a rapid

increase in the proportion of individuals developing contractures

subsequent to transition to the wheelchair.

Knee contractures- Again, no knee contractures occur when the

individual transitions to the wheelchair, and the knee then becomes

statically positioned in flexion and any rapid acceleration in the

development of contractures is subsequent to transition to the

wheelchair in Duchenne Dystrophy.

Hip flexion contractures- Again, with transition to the wheelchair,

on come hip flexion contractures. So the child takes on essentially

the form of the wheelchair as their static position in flexion at the

hip, flexion of the knee and they are no longer weight bearing to the

ankle because of the tremendous replacement of the muscle by fat and

scar tissue. Again, this point of static positioning of muscle fiber

leads to contractures in Duchenne Muscular Dystrophy. Children who

are ambulating, their arms are positioned down at their side in

extension. Children who are sitting in wheelchairs rest their elbow

on the elbow rest. So, sure enough, elbow flexion contractures.

Again, with transition to the wheelchair, on come the elbow flexion

contractures. Again, this is a direct result of static positioning

in a sedentary situation. This is the classic picture we see

clinically with hip flexion contractures, knee contractures and

equinovarus contractures due to lack of weight bearing through the

lower extremities.

There are a number impairments in Duchenne Muscular Dystrophy which

reduce physical activity. We have mentioned that weakness is

probably the most important. This is due to the dystrophinopathy as

well as disuse. Fatigue, and we will hear more about this by Dr.

later in the session. Fatigue can actually lead to reduced

physical activity in Duchenne Dystrophy.

Cardiopulmonary involvement- If these individuals have a

cardiomyopathy, we will hear more about cardiopulmonary involvement

from Dr. Bernauer. I eluded to contractures which obviously have an

impact on physical activity and then excessive weight gain. What

about weight gain? In Duchenne Dystrophy, after these individuals

transition to a wheelchair, they become more sedentary and we

actually see an increase in obesity, but later on in the disease as

they reach an end-stage period of time, their work of breathing

increases and they actually become hypercatabolic and we actually see

tremendous cacchexia in these young people, late in the stages of

disease.

Next we have our data on weight gain in Duchenne Dystrophy. At 9-13

years of age, in the transition to the wheelchair, Duchenne Dystrophy

individuals actually gain excessive weight per year relative to

controls. Then, later in the disease, 17-21, there is actually

tremendous weight loss in this disorder relative to controls. Again,

it really depends on the stage of the disease what the weight gain

dynamics are.

What about some examples of functional limitation? The NCMRR model

defines functional limitation as a restriction or lack of ability to

perform an action in a manner or within a range consistent with the

purpose of an organ or organ system. So, examples of functional

limitation would be decreased velocity of ambulation, decreased

distance achieved per unit time or metabolically inefficient

ambulation in Duchenne Dystrophy.

Again, what about walking speeds in 6-10 year old children with

Duchenne Dystrophy. There was a controlled speed of 79 meters per

minute, Duchenne Dystrophy 48 meters per minute. Sprint velocity 233

meters per minute in the control, 75 meters per minute in the

Duchenne population. Distance achieved in 10-minute walk, 770 meters

in the control. What is interesting is that in ten minutes, these

patients travel 339 meters. The average velocity over ten minutes

would actually be 33 meters per minute. So actually they start out

with comfortable ambulation and start out ambulating at 48 meters per

minute. By the time they are approaching 10 minutes, they are down

to 33.9, as an average velocity, so there may be some fatigue

component here that we may be dealing with. In fact, if you look at

the percent of Duchenne individuals who are able to walk a given

distance in ten minutes, the blue line represents the controls. 100%

of the controls get to 700 meters at ten minutes and you can see

this, it almost looks like a survival curve here, of a reduced

numbers of dystrophy patients able to achieve those greater distances

over ten minutes.

Recently, we have the advent of portable metabolic carts, which

actually allow us to assess energy expenditure during real world

locomotion in individuals with quite substantial mobility

impairments. We have actually been able to test children down to age

five with these portable metabolic carts, Cosmed, breath-to-breath

cart, the K4b2 being one example. We are also able to assess energy

expenditure during wheelchair propulsion. There is a young man with

Duchenne Dystrophy who is pushing a wheelchair and we are actually

able to collect data, energy expenditure during wheelchair

propulsion; heart rate shown in the pink, oxygen uptake VO2, which is

in the blue, and again, increased energy expenditure during

wheelchair transfer from the gurney onto the wheelchair. There is

the transfer and comfortable wheelchair propulsion over ten minutes,

rest and return back to baseline and new data obtained during

wheelchair sprint.

I wanted to digress one moment to focus on the issue of metabolic

penalty of obesity. We actually assessed this and issues of economy

of movement in able-bodied obese children and able-bodied control

children between the ages of 6-10. These were actually extremely

obese children between the ages of 6-10. We have actual fat tissue

content by DEXA of over 20 kg in these obese children versus 6 kg of

fat tissue in control subjects. What we found was a striking

difference in the meters traveled per liter of O2 consumed,

essentially a measure of economy of movement, sort of like miles per

gallon. We saw this across the age range between 6-10, so essentially

the obese children here down below and were sort of like SUVs,

whereas the able-bodied children were essentially economy vehicles.

So, given there is a metabolic penalty of excessive adipose tissue to

individuals who are able-bodied, and there may well be even greater

metabolic penalty of excessive adipose tissue in individuals with

weakness, such as neuromuscular diseases. We have measured oxygen

cost during walking and sprinting in Duchenne Dystrophy. There are

oxygen cost values which have significant differences in walking and

100 meter sprint. The Duchenne group has an increased oxygen cost,

or greater oxygen consumed per meter traveled in this calculation and

again, there is a direct relationship between velocity of information

and oxygen cost. So, the blue indicators show high velocities, lower

or more efficient oxygen costs and then as the velocity slows, the

oxygen cost increases. So, as these individuals are more

metabolically inefficient, they slow their speed at which they

ambulate.

Heart rate in Duchenne Dystrophy during the 100 meter sprint, we can

collect heart rate and option uptake data during the 100 meter

sprint. The Duchenne individual starts actually with a heart rate

greater than their control counterparts and then they have this

rather flat response here, as they sprint over a 100 meter distance,

you can see this linear increase in heart rate in the control

population. Again, the ability of the Duchenne to increase their

heart rate appears to be diminished and similarly the ability for

them to increase their VO2 a rather flat curve here as they sprint

over the 100 meter distance and again a more linear increase in

oxygen uptake in the control population. So, again, a baseline,

relatively equivalent values, but substantial differences in VO2 with

a 100 meter sprint. These are in fairly young children. In fact, we

can normalize VO2 per grams of lean tissue by DEXA to see if this

makes any difference in the Duchenne population versus control. And,

again, we can look at the efficiency of locomotion during the sprint

and can get similar data here with the controls here, and as we slow

velocity we see more metabolically inefficient locomotion in the

Duchenne population.

Finally, to end, disability. The NCMRR model defines disability as

the inability or limitation in performing tasks, activities and roles

to levels expected within physical and social contexts. An example

of disability would be the inability to exercise, decreased daily

physical activity in the community in Duchenne muscular dystrophy.

Again, with utilizing quantitative activity monitoring systems, we

have been able to show quite marked reductions in physical activity

measured quantitatively with the Duchenne population. There is Step

Activity Monitoring data of 24 hours in the able-bodied child.

Essentially, we can see these high intensity periods, total steps per

day of 7,200 over a 24-hour period of time. We age-matched that

Duchenne patient with 1,800 total steps per day, again a marked

decrease in physical activity measured quantitatively. Indeed, when

we look at step activity intensity, the control subjects take far

more steps at the high activity level, more steps than the Duchenne

at the moderate activity level and equivalent steps per day at the

low activity level. Therefore, there seems to be dramatic

differences in the Duchenne versus the control populations at the

steps taken at the high activity levels. Again, total steps per day,

control….. and then minutes per day at the high activity level 72

minutes per day in the controls versus only 43 minutes per day in the

Duchenne population.

The NCMRR model also discusses societal limitation and defines that

as a restriction, attributable to social policy or barriers

(structural or attitudinal) which limits fulfillment of roles or

denies access to services and opportunities that are associated with

full participation in society. An example being a teenager in a

power wheelchair with Duchenne dystrophy is not able to participate

in PE because adaptive PE is not available at the school or is poorly

developed in the school system, as an example of societal

limitation.

To end, I think the number of needs here for scientifically based

recommendations concerning optimal exercise guidelines, optimal

guidelines for physical activity. Obviously, when it comes to issues

of safety, we need disease specific recommendations relating to types

of exercise, eccentric and so forth. With regard to safety, we

really need disease specific recommendations. We also need

recommendations regarding the minimum frequency, amount of exercise,

amount of physical activity, duration of exercise required for

beneficial health effects. Finally, in individuals with greater

degrees of weakness, we need development of novel approaches to

enhance levels of physical activity in persons with varied severities

of impairment due to neuromuscular diseases.

Thank you, Craig.

Carlsen: When you talked about progression from leg muscle to

four-limb muscle, what happens to the diaphragm?

Craig Mc: The diaphragm, interestingly, is relatively spared

earlier in the course of the disease. In fact, in younger patient

population, there is actually a greater decline in maximal expiratory

pressure, static airway pressures, which are more of a measurement of

chest wall, accessory muscles of respiration. Whereas they had a

relative preservation of maximal inspiratory pressures related to the

maximum expiratory pressures. There is actually a greater decline in

skeletal muscles, accessory muscles of respiration, relative

preservation of the diaphragm. Of course, late in the disease, the

diaphragm starts to become quite involved as well.

Greg : In the X-model, the diaphragm has dystrophic changes way

ahead of the skeletal muscles, and actually I have slides on that

tomorrow. There are some interesting differences between human

dystropinopathy and mouse, and that is one of them, I think.

Ralph Nitkin: I was struck by the rapid progression to contractures,

even in the elbows, where the kids presumably using their hands to

move the wheelchair. I was wondering, how much of that is a unique

case of muscular dystrophy where it could actually be due to the

pathology itself as opposed to the disuse syndrome? Do you have any

other parallel studies with kids with other disorders with a

progression to a wheelchair with the onset of contractures?

Craig Mc: I think that definitely the connective tissue

character is different and, in fact, there is probably some

heterogeneity among subjects as well. We see some subjects who have

minimal or just moderate contractures and other subjects who have

rather profound pseudohypertrophy connective tissue replacement and

quite profound contractures. The other issue that is important here

is that generally when we see contractures in individuals with less

than antigravity muscle strength. So, we are unable to volitionally

put their limbs through a full range of motion due to weakness. So,

a combination of static positioning plus severe muscle weakness that

precludes the individual from extending their muscle through its full

available range of motion is generally set up for contractures.

Usually, we don't see those contractures forming in more slowly

progressive or mild neuromuscular disease conditions where the

individual, just with functional activities, reaching overhead and so

forth, can pull the muscle through full range of motion. So, it

seems that this weakness places the muscle group in a static position

really seems to be the problem in the Duchenne population. There are

other populations where congenital muscular dystrophies where they

have congenital contractures on the basis of interuterine

positioning. Emery-Dreifuss, as Dr. eluded to earlier, made a

quite profound elbow flexion contractures early on and there appears

to be something different about the muscle fiber ultrastructurally as

well as probably the connective tissue in those populations.

Bob Fitts: On speculated data on the muscle force per lean tissue in

patients, I wonder if you have any data that would explain it. Is it

loss of contractile protein associated with that, or is there some

other non-uniformity of sarcomeres or what is the explanation for

that loss of force per lean tissue?

Craig Mc: Again, I can't really explain it ultrastructurally,

whether it is a contractile phenomenon. I clearly cannot explain it

purely on the basis of loss of fiber or loss of lean tissue. There

appears to be some contractile abnormalities as well. That is an

excellent question and probably some animal work will probably be

necessary to really get that issue.

Bob Fitts: Didn't he work on diet in, for example, essential amino

acid supplements seem to help in weightlessness conditions, and I am

wondering if anything like that been tried with these disease states.

Craig Mc: Dr. Kilmer, do you…

Kilmer: I have not seen any work specifically with amino acid

supplements. Almost every other kind of supplement has been tried…

DR. MCDONALD: I think there has been some high branch chain amino

acid diets that have been used, but not in any large series, though.

Usually these are anecdotal reports that have been done for the most

part. These individuals seem to be hypercatabolic late in the course

of the disease and there appears to be a tremendous loss of protein

that is occurring late in the course of the disease. In some people,

we have actually advocated high protein diets for these young people

later in the course of the disease, just because of the profound loss

of protein.

Bob Fitts: Is the loss of protein due to accelerated degradation, or

is there a drop off in synthesis or do we know that?

Craig Mc: Both.

Fowler: The substance treatment of neuromuscular diseases

follow exactly the same course as ergogenic age in athletes. It

started out with amino acids and protein supplements back in the 40s,

when they started feeding people this, and then moved its way up, and

most recently it has been used in anabolic steroids. There have been

a lot of studies now I think with creatin.

Greg : A good example of that has been oxidative stress and to

my knowledge, just pumping either animals or humans full of

antioxidant cocktails does not seem to make a huge difference as far

as cellular oxidative stress.

Fowler: Vitamin E was a big treatment way back…..

Tom Rando: People have tried a variety of antioxidants systemically

in mice and humans, usually in very small anecdotal studies, open-

ended a few months, so they are not very well studied. The other

ongoing trial, in addition to creatine, there is a glutamine

administration trial going on along with the creatin right now for

boys with DMD but that is just getting going, nothing yet that I know

of.