therapeutic approaches targeting skeletal muscle plasticity after sci

Therapeutic Approaches Targeting Skeletal Muscle Plasticity after SCI

Chris Gregory

Assistant ProfessorDepartment of Health Sciences &

ResearchMedical University of South Carolina

Health Science SpecialistResearch Service

Ralph H. Johnson VAMC

July 17, 2012

Disclosure of PI-RRTC Grant

• James S. Krause, PhD, Holly Wise, PhD; PT, and Emily Johnson, MHA have disclosed a research grant with the National Institute of Disability and Rehabilitation Research.

• The contents of this presentation were developed with support from an educational grant from the Department of Education, NIDRR grant number H133B090005. However, those contents do not necessarily represent the policy of the Department of Education, and you should not assume endorsement by the Federal Government.

Accreditation• The Medical University of South Carolina is accredited by the Accreditation

Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The Medical University of South Carolina designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

• In accordance with the ACCME Essentials &Standards, anyone involved in planning or presenting this educational activity will be required to disclose any relevant financial relationships with commercial interests in the healthcare industry. This information is listed below. Speakers who incorporate information about off-label or investigational use of drugs or devices will be asked to disclose that information at the beginning of their presentation.

• The Center for Professional Development is an approved provider of the continuing nursing education by the South Carolina Nurses Association an accredited approver by the American Nurses Credentialing Center’s Commission on Accreditation

Disclosure of Presenter

• Chris Gregory, PhD, PT, has disclosed research grants with the Department of Veteran’s Affairs, American Heart Association, South Carolina Spinal Cord Injury Research Fund and NIH/NINDS.

Axon Regeneration

Prevent 2°Damage

Create Bridges

Replace Dead Cells

Outline

• Skeletal muscle adaptations following SCI– Acute vs. Chronic

• Secondary Health Conditions associated with alterations in skeletal muscle after SCI

• Effects of exercise training on skeletal muscle after SCI

• Health-related benefits of exercise in persons with SCI

Skeletal Muscle

Spinal Cord Injury

Secondary Conditions:NIDDMCVD

ObesityDyslipidemiaDecreased fitness

Osteoporosis

↓ Bone Density ↓ CV Function

Physical Inactivity / Muscle Unloading

Secondary conditions following SCI

Increased risk of cardiovascular disease (Kocina, 1997)

Leading cause of death after 20 yr DOI~90% > risk of heart attack relative to un-injured~228% > mortality risk from CVD46% of patients over 30 die from CVDDecreased HDL

Increased risk of NIDDM (Bauman, 2000)

~4x incidence of NIDDM after SCI ~65% have impaired CHO metabolism vs 15% in un-injured population

Decreased bone density~50% reduced in 100% of population

• Complete injury– Absence of sensory and motor function in the lowest sacral

segment

• Incomplete injury– Partial preservation of sensory and/or motor function below

the neurologic level

ASIA Impairment Scale:

• A No motor or sensory function in the lowest sacral segment

• B Sensory but not motor function is preserved in the lowest sacral segment

• C Less than ½ of the key muscles below the (single) neurological level have a grade 3 or better

• D At least ½ of the key muscles below the (single) neurological level have a grade 3 or better

5 – Normal strength4 – Full ROM with < normal strength against resistance3 – Full ROM against gravity 2 – Movement with gravity eliminated 1 – Palpable contraction but no movement0 – Total paralysis

Hillegass and Dudley 1999

Able-bodied male C5 complete SCI male

Skeletal muscle adaptations following “Chronic” SCI

Severe Muscle Atrophy (60-75%)

Quadriceps muscle CSA and total quadriceps muscle volume in SCI and able-bodied (AB) individuals.

Olive J L et al. J Appl Physiol 2003;94:701-708


Control

SCI

Conversion to predominately fast fibers

Martin et al. 1992 Gregory et al. 2003

~66%

~36%

Bickel et al 2004

Muscle Fatigue

Olive J L et al. J Appl Physiol 2003;94:701-708

Muscle Fatigue

PCr recovery curves following NMES for (A) control and (B) SCI individual.

Muscle Fatigue

Muscle Injury

Bickel et al 20042 ± 1 % 25 ± 6 %

Long-term SCI

Specific Tension - force per unit area.Torque (Nm) = 3.74 x stimulated CSA (cm2) - 14.37, (R2 = 0.93, p < 0.05)

Bickel et al. 2004

“Chronic” SCI Muscle

• Severe muscle atrophy

• Conversion to predominately fast fibers.

• Increased fatigability

• Increased susceptibility to injury

• Force generating capacity (relatively) maintained

Individuals years after SCI have been reported to have muscles that are small, highly fatigable and susceptible to damage; but still produce adequate force relative to their size.

(Grimby 1976, Rochester et al. 1995, Hillegass and Dudley 1999 )

Able-bodied male C5 complete SCI male


Pre-injury 12 weeks post-injury

“Classic” Brown-Sequard syndrome

Skeletal muscle adaptations following “Acute” SCI

Muscle Atrophy

MRI - 6, 12, 24 weeks after injury

Thigh Muscles

- Hamstring (-14%)

- Adductors (-16%)

- Quadriceps (-16%)

Castro et. al. 1999a

Muscle Atrophy

MRI - 6, 12, 24 weeks after injury

Shank Muscles

- TA (5% decrease, NS)

- Soleus (-12%)

- Gastrocnemius (-24%)

Castro et. al. 1999a

Muscle Atrophy

QF -42%

Hamstring -44%

Adductor -31%

Gastroc -46%

Soleus -32%

TA -20%

SCI vs. Controls

55

60

65

70

75

80

% C

SA

of

AB

0 10 20 30 40 50 60

Time (weeks after injury)

EMS

Dudley et al. 1999

Muscle Atrophy

Fiber type

Castro et. al. 1999b

* Data from m. Vastus Lateralis

Enzyme changes

Castro et. al. 1999b

CSA

SDH

GPDH

SDH - Kreb’s cycle (aerobic)

GPDH - glycolytic enzyme (anaerobic)

Muscle Fatigue

Increased muscle fatigue after SCI despite the alterations in muscle

Castro et al 1999b Bickel et al 2004

“Acute” SCI Muscle

• Muscle specific atrophy

• Change in fiber type composition.• (IIa to IIx)

– No decrease in % slow muscle in first 6 months

• Energy supply/energy demand apparently unaltered.

• Fatigability is increased compared to controls

Relative differences in individual muscle CSA between the more-affected limb following incomplete SCI vs. control subjects.

Muscle AtrophyIncomplete SCI

“Chronic” SCI Bone

SCI results in a dramatic loss of bone and a marked increase in fracture incidence

Dauty et al. 2000; Modelesky et al. 2004

- Chronic SCI results in a 50-70% demineralization and is correlated with duration of injury

- Following complete SCI, bone loss proceeds at a rate of ~1% per week for the first 6-12 months- Microgravity = 0.25% /week- Bed rest = 0.1% /week- Menopause 3-5% /year



Modelesky et al. 2004



SCI Control

Distal Femur

Proximal Tibia

Modelesky et al. 2004


SCI: r = 0.90 and 0.83Modelesky et al. 2004

Relationship between muscle volume and cortical bone volume and BMC remains strong

Femoral artery diameter

Peak blood flow

Vascular Response to SCI

In the next several decades, a cure for SCI is a realistic possibility. Without a means to preserve the musculoskeletal integrity of paralyzed lower limbs, people injured today with SCI will be "inappropriate candidates" for reintroduction to

standing and walking, should a cure be found.

So What?

Is it possible to elicit changes in muscle and bone years after SCI?

Early studies suggest an inability to increase muscle size in subjects years after injuryOther studies do report modest muscle hypertrophy (0-15%) following NMES cycling

Is this enough?Limitations?

Program design

Aerobic/endurance exercise does not

Resistance exercise increases muscle size &

strength

SCI - Resistance Training

2 days/week x 6 months

Electrical stimulation (30 Hz trains of 450 µsec biphasic pulses)

4 sets of 10 knee extensions Resistance - cuff weights

All training performed at subjects’ homes

55

60

65

70

75

80

% C

SA

of

AB

0 10 20 30 40 50 60

Time (weeks after injury)

EMS

Dudley et al. 1999

4 sets of 102 days per week for 8 weeksTotal contractions = 640

Molecular signals

Effects of (NMES)-induced exercise on the expression and/or accumulation of mRNA for components of the muscle insulin-like growth factor (IGF)-I system

Bickel et al 2003

After 6 months of training: Subjects were using between 14 - 30 pounds for resistance at the ankle. QF muscle size increased ~60% in both thighs.

Before 6 Months3 Months

SCI - Resistance Training“Chronic”

n = 5

*p < 0.05, 3 Mo. Vs. Before

‡ p<0.05, 6 Mo. vs. 3 Mo.

Average AB muscle size (Castro et al. 1999)

RIGHT THIGH LEFT THIGH


34

49

58

37

52

62

Mahoney et al 2005

Left Thigh Muscle CSA

0

10

20

30

40

50

60

70

80

S1 S2 S3 S4 S5 Mean

Mu

sc

le C

SA

(c

m2)

BEFORE

AFTER


FIGURE 1 . Axial MR Images of thigh (A) and knee extensors skeletal muscles (B) and %IMF (C) before and after RT + diet versus diet groups.

Gorgey et al., Med & Sci Sports & Exer. 44(1):165-174


Health-related consequences of increasing muscle mass

Electrically stimulated RT significantly lowered plasma glucose response during OGTT (n=5)

0

30

60

90

120

150

180

0 60 90 120

Pla

sm

a g

luco

se

(mg/d

l)


Body composition Pre Post

Total (lb) 153.22 ± 9.32 157.76 ± 9.11*

Muscle (lb) 96.8 ± 5.61 100.0 ± 5.47*

Bone (lb) 6.03 ± 0.37 5.99 ± 0.39

Fat (lb) 50.42 ± 5.10 51.78 ± 4.98

Neural factors

Motor score 46.35 ± 4.90 49.35 ± 5.31*

Sensory score 91.59 ± 11.32 97.88 ± 11.52*

Metabolic factors

HDL cholesterol (mg/dL) 34.27 ± 2.00 30.56 ± 2.11*

LDL cholesterol (mg/dL) 102.65 ± 6.20 105.54 ± 5.49

Total cholesterol (mg/dL) 157.91 ± 6.36 156.32 ± 6.65

Triglyceride (mg/dL) 104.92 ± 26.90 101.07 ± 25.46

CRP (mg/L) 15.92 ± 1.57 12.94 ± 0.78*

IL-6 (pg/ml) 4.91 ± 1.10 3.79 ± 0.52*

TNF-α (pg/ml) 11.82 ± 0.63 11.31 ± 0.62*


Fig. 1. Absolute bone mineral density (BMD) for control (■) and for the left (□) and right (▨) sides of subjects with SCI before training. The three regions are statistically different from each other, both for the control and SCI subjects (p < .05). The lower bone densities in the SCI subjects are also significantly different from control subjects in all three regions (indicated by the asterisk above the bars). The BMD expressed as a percentage of control values are indicated at the bottom of the bars


Fatigue before training (6–12 months prior to the initiation of this study), at 8 and 12 weeks, and post-training (18 weeks). Data are illustrated as mean SD. Fatigue decreased as training progressed (P=0.008). Although the pretime point (ie, 0 on the graph) occurred some time before the training program began, the protocol and test administrators were identical for each test administration and subjects had not changed activity levels during the interim period. *P=0.014 for comparison with pretraining. †P=0.016 for comparison with pretraining


Twice weekly, 4 sets of 10 reps of dynamic knee extension

• Quadriceps muscle size increased ~70% in both thighs

• Glucose tolerance was improved

• Bone density increased

• Muscle fatigue was reduced 60%

Health-related consequences of increasing muscle mass

Low physical fitness is associated with increased risk of CVD mortality in non-injured individuals (Blair et al 1995)

Low physical fitness = Peak VO2 < 20 ml/kg/min

Decrease risk of CVD by 50% by increasing peak VO2 by 7 ml/kg/min8% risk reduction with 1.75 ml/kg

Future Directions

Peak VO2 measures on SCI patients range from 12-20 ml/kg/min.

Some improvements in peak VO2 realized after cycling, arm ergometry, circuit training and ambulation training (e-stim).

Circuit training (Jacobs et al. 2000) Peak VO2 increased 30%(19 - 24 ml/kg/min)

FES cycling (Pollack et al. 1989) Peak VO2 on increased 17% (1.2 L/min - 1.4 L/min)

Ambulation training VO2 increased 33% (1.2-1.6 L/min)

Future Directions

Small peripheral muscle mass seemingly limits oxygen consumption (Hopman et al 1998)

For example:Take an AB person and exercise one limb

This would not stress central cardiovascular function because of the limited mass of active muscle

Future Directions

Muscle mass and peak VO2

Can NMES resistance exercise increase muscle mass to allow for sufficient training stimulus to evoke large increases in fitness?

Future Directions

Optimization of Electrical Stimulation Patterns

Future/Current Directions

- Reduce fatigue?- Resistance and aerobic training

Center of RotationMagnetic Brake/ClutchTorque TransducerEncoder Assembly

Interface Box

Flexion/Extension Electrode Pair


Center of RotationMagnetic Brake/ClutchTorque TransducerEncoder Assembly

Interface Box



Future/Current DirectionsIncomplete SCI

Impaired neuromuscular function limits locomotor ability following incomplete SCI and rehab programs specifically targeting muscular

impairments will attenuate existing deficits and improve walking.

• Progressive RT (2-3x/week, 12 weeks)– 2-3 sets of 6-12 reps (70-85% 1 RM)

• Target: CSA & Strength

• Ballistic Training– 2-3 sets, 12-20 contacts

• Target: Time to peak tension; Power

Future DirectionsIncomplete SCI

Acknowledgements

Gary Dudley PhD Manning Sabatier PhD

Scott Bickel PT, PhD Chris Black PhD

Mark Bowden PT, PhD Jill Slade PhD

Ed Mahoney PhD Arun Jayaraman PT, PhD

Krista Vandenborne PhD Prithvi Shah PT, PhD

Funding: National Institutes of Health RO1HD40850

therapeutic approaches targeting skeletal muscle plasticity after sci

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