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Functional Recovery of the
Musculoskeletal System
Following Injury – Leveraging
the Large Animal Model
Sarah Greising, PhD
Kinesiology
University of Minnesota
Associate Professor
Functional Recovery of the
Musculoskeletal System Following Injury -
Leveraging the Large Animal Model
Sarah Greising, PhD
Associate Professor
Henry L. Taylor-Arthur S. Leon Professorship
grei0064@umn.edu
08. December. 2022
Skeletal muscle function
and physiology Limited regenerative
potential of skeletal
muscle
VML injury
Small to large animal models
Functional recovery
Grogan & Hsu, J Am Acad Orthop Surg 2011
Injury in which a critical portion of a muscle or muscle
unit is abruptly removed due to trauma or surgery
Outcomes associated with VML injury
• Persistent functional deficits
• Loss of range of motion
• Chronic disability
Gentile et al., 2014 Garg et al., J Ortho Res 2015
Irrecoverable loss of
contractile tissue and
strength
No current clinical, surgical, or
rehabilitative standard of care
that address the loss of
endogenous material
necessary for muscle
regeneration or directly impact
the soft tissue
Loss of Strength
Shift of Angle of
Peak Torque
“Longer Muscle Length”
Loss of Active
Range of Motion
Garg et al., J Ortho Res 2015
Biodex Isokinetic testing
60˚/s; 10 Work Loops;
Start at 0˚ - End active range of plantarflexion
• Military trauma
On an annual basis VML can result secondary to:
• 150,000 open fractures
• 36,000 industrial or farm accidents
• 30,000 gunshot wounds and related trauma
• 80 shark attacks
• 13,000 soft-tissue cancers
• 4,000 cleft lip and palate
Trauma
Physiologic
Orthopaedic Trauma
US economic burden to trauma is in excess of $400 billion yearly
Soft tissue trauma
• 2 million hospitalizations
• 9 million bed days
• 6.5 million outpatient visits
• 18 million emergency room visits
• 64 million physician's office visits
US Department of Defense
• $42.2 billion in initial care
• $108.8 billion in lifetime disability benefit cost to injured service
members
The outcomes of these various forms of orthopaedic injuries is chronic
disability in which muscle regeneration is not possible
1) Surgical, regenerative medicine, and/or rehabilitation approach targeted at
regenerating the lost muscle
2) Approaches to improve the remaining muscle and prevent further
degradation, i.e., remodel and/or adapt to the new cellular condition
3) Understand the pathophysiology of the both the injury and muscle
remaining
4) How to improve function, i.e., functional recovery, chronically after injury
Various models in literature
• Abdominal wall, latissimus dorsi,
tibialsis anterior, quadriceps,
posterior compartment muscles
• 10-50% of the muscle volume
with functional deficits exceeding
the volume lost
Southern et al., Sci Rep 2019
Small & Large Animal Model of VML Injury
Small & Large Animal Model of VML Injury
Porcine peroneus
tertius muscle (~5
g; 20% volume)
Mouse & rat tibialis anterior (TA) muscle Mouse gastrocnemius,
soleus, & plantaris muscles
Pollet & Corona, MMB 2016 & Greising et al., Sci Rep 2017
Chronic functional
impairment
Long-term dysfunction, reduced mobility
and physical activity, co-morbidities,
delayed amputation
Chronic loss of
skeletal muscle
Pathophysiology
Clinical Distinction
Irrecoverable
Volumetric
muscle loss
injury
Lack of endogenous
regenerative ability
Increased
pathologic fibrosis
Chronic and heightened
inflammation
Altered muscle
architecture/force transmission
Chronic neural
dysfunction
Metabolic maladaptivity
Satellite cell dysfunction
Clinical Outcomes
Inability to respond to
rehabilitation
Sorensen et al., 2022
Corona et al., JoVE 2021
Pollet & Corona, MMB 2016
Corona et al., JoVE 2021
Corona et al., JoVE 2021
Length control
Corona et al., JoVE 2021
Chronic functional
impairment
Long-term dysfunction, reduced mobility
and physical activity, co-morbidities,
delayed amputation
Chronic loss of
skeletal muscle
Pathophysiology
Clinical Distinction
Irrecoverable
Volumetric
muscle loss
injury
Lack of endogenous
regenerative ability
Increased
pathologic fibrosis
Chronic and heightened
inflammation
Altered muscle
architecture/force transmission
Chronic neural
dysfunction
Metabolic maladaptivity
Satellite cell dysfunction
Clinical Outcomes
Inability to respond to
rehabilitation
1) Simple example of scale up with a HGF loaded biomaterial
2) Complex approach of scale up with pharmacologic treatment
of fibrosis
3) Pathophysiologic understand of impairments to support
future scale up
a) Neural
b) Metabolic
4) Summary and next steps
Combined treatment
approach
Increased pathologic
fibrosis
An overaccumulation of
extracellular matrix
deposition during the
repair process
Impaired healing and
regeneration
Greising et al., BMC Musc 2018
Mouse VML model
 2 Fold increase in
passive torque
 1-2 Fold increase in
collagen content
 Indicating increased
stiffness
Hoffman et al., Con Tiss Res 2021
 Increased
fibrosis and
denser collagen
in the muscle
remaining
 Suggesting
increased
stiffness
 Conserved increase in collagen
content between the rodent and
pig
 Suggesting increased stiffness
Corona et al., Tis Eng A 2020
Awasthi et al., Onco Targets Therp 2015
Anti-Fibrotic Treatment Nintedanib
Intracellular tyrosine kinase inhibitor that
targets fibroblast growth factor receptor
(FGFR) 1-4, platelet-derived growth
factor receptor (PDGFR) α/β, vascular
endothelial growth factor receptor
(VEGFR) 1-3, and the Src family of
tyrosine kinases Lck, Lyn, and Flt-3
I
n
j
u
r
y
N
a
i
v
e
C
o
n
t
r
o
l
V
M
L
A
l
o
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e
V
M
L
+
N
i
n
t
e
d
a
n
i
b
0
200
400
600
800
Peak
Torque
(mN*m/kg)
Mouse VML model
Awasthi et al., Onco Targets Therp 2015
Anti-Fibrotic Treatment Nintedanib
Intracellular tyrosine kinase inhibitor that
targets fibroblast growth factor receptor
(FGFR) 1-4, platelet-derived growth
factor receptor (PDGFR) α/β, vascular
endothelial growth factor receptor
(VEGFR) 1-3, and the Src family of
tyrosine kinases Lck, Lyn, and Flt-3
Pig VML model
Corona et al., Tis Eng A 2020
 Anti-fibrotic treatment diminished the VML-
induced change in stiffness
 Non-repaired and non-treated VML muscle
have a 4-7 fold increase in stiffness 1-month
post-injury
Superficial
Deep
Corona et al., Tis Eng A 2020
 Greater force deficit in the anti-fibrotic treated
group than the VML non-repaired, non-
treated
 One-month post-VML there is a similar deficit
of ~35% when normalized for muscle size
Corona et al., Tis Eng A 2020
 Preservation of directionality of the natural wound healing response
 In many genes, the anti-fibrotic treatment following VML injury consistently affected
expression by attenuating the magnitude of upregulation
 As opposed to completely inhibiting upregulation (or downregulating)
Corona et al., Tis Eng A 2020
Fibrosis Wound healing
Increased pathologic fibrosis
An overaccumulation of extracellular matrix deposition during
the repair process
Impaired healing and regeneration
How do we optimize treatment delivery or timing?
Keep this TGFβ independent?
How to integrate with other approaches?
Chronic neural
dysfunction
Full maturation of
regenerated or repaired
muscle fibers is
dependent on fiber
innervation
Laminin/Neurofilament
persistent
functional deficits
maintained
descending
axons
maintained α-motor neurons,
but persistent axotomy
Corona et al., Mus Nerv 2018
 Retained but limited capacity for reinnervation
Pig VML model
 No motor neuron death, but
significant axotomy
 Notably, motor neurons
have retained capacity for
reinnervation
maintained α-motor neurons
 Retained but limited capacity for reinnervation
Nuclei (DAPI) / Axons (2H3-SV2 & S100) / NMJ αBTX
 What about innervation
at the fibers?
Sorensen et al., J Appl Phys 2021
Secondary enervation and the chronic appearance of
sprouting and poly-innervation are part of the sequela of injury
Contribute to the chronic loss of muscle function post-VML
injuries
The maintenance of NMJ size and complexity indicate the
potential for NMJs to be reinnervated, supportive to retention
of motor neurons
Pre-synaptic (2H3-SV2) / Post-synaptic (αBTX)
Post-synaptic NMJ (αBTX) / Axons Pre-synaptic (2H3-SV2) / Nuclei (DAPI) / S100
tSC co-localization
What about the specialized terminal Schwann cell (tSC)?
Post-synaptic NMJ (αBTX) /
Axons Pre-synaptic (2H3-SV2) /
Nuclei (DAPI) / S100 (tSC co-
localization)
Hoffman et al., In Review
Delayed increase in tSC
number
Possible pathologic
trophic activity
Can the potential to reinnervate
be targeted?
Herceptin: Monoclonal Antibody
designed to target the ErbB2/HER2
receptor in Breast cancer cells.
In skeletal muscle
Neuregulin activates the ErbB/HER
receptors for downstream activation
of nerve development and other
cellular processes
Has shown a paradoxical role in
promoting axon outgrowth following
inhibition
Sorensen et al., In Review
 No functional
improvement
 Able to mitigate
secondary denervation
and pathologic NMJ
characteristics
Sorensen et al., In Review
 Although paradoxical,
inhibiting the ErbB2
receptor chronically
Chronic neural dysfunction
 Prolonged motor neuron axotomy and secondary denervation may have
considerable impact on the functional capacity
 Optimistically, there is a lot of remaining potential
 How do we optimize treatment delivery or timing?
 How do we optimize the development of regenerative medicine approaches
to support reinnervation, considering an overactive local environment?
 Understand and target supporting aspects of the NMJ like the tSCs, along
with all the other aspects (e.g., satellite cells, FAPS, growth factors, immune
cells) is important to support ongoing potential for stabilization and
reinnervation in efforts to support long-term functional recovery
Metabolic maladaptively
Lack of standard metabolic
response locally
Whole-body implications
Acute and local destruction of the mitochondrial network that
corresponds to mitochondrial dysfunction
Southern et al., Sci Rep 2019
Distance from Injury Site
Southern et al., Sci Rep 2019
Greising et al., BMC Muscul Dis 2018 Southern et al., Sci Rep 2019
Injury-induced increase in mitochondrial content in the remaining muscle, but
they have a reduced oxidative capacity both acutely and chronically
S h a m VM L
0
1
2
3
4
C
S
(n
m
o
l/s
/m
l)
*
S h a m VM L
0 .0
0 .2
0 .4
0 .6
F
IS
1
/G
A
P
D
H
(
r
.l.u
.)
* *
Chao et al., J Appl Phys 2019
Pig VML model Mouse VML model
Mitochondrial respiration states are impaired across
the respiratory states chronically
McFaline-Figueroa et al, Tis Eng A 2022
Electron conductance is slowed in VML-
injured muscle compared to injury naïve
muscle and this is associated with a
greater mitochondrial membrane potential
Impaired carbohydrate lipid oxidation
oxygen consumption (JO2) at different ATP Gibb’s
free energy states for carb vs. fat substrate
McFaline-Figueroa et al, In Review
Dalske et al., PLOS 2021
Injury-induced impairment in whole-body metabolism
M
o
re
lip
id
s
M
o
re
c
a
r
b
s
Decreased carbohydrate oxidation and increased lipid oxidation
Due primarily to changes in substrate oxidation and fuel selection
N
a
i
v
e
V
M
L
0 .0 0
0 .0 5
0 .1 0
0 .1 5
d
e
lta
R
E
R
*
0 .7
0 .8
0 .9
1 .0
R
E
R
N aive
V M L
M
o
re
lip
id
s
M
o
re
c
a
r
b
s
A c tiv e
P h a s e
In a c tiv e
P h a s e
Raymond-Pope et al., In Review
Metabolic maladaptively
Reduced mitochondrial function and enzymatic activity
Chronic metabolic rate and RER reductions with no change in
activity
Can we optimize a treatment?
How to correct mitochondrial function for long term health?
How to integrate with other approaches?
1) Simple example of scale up with a HGF loaded biomaterial
2) Complex approach of scale up with pharmacologic treatment
of fibrosis
3) Pathophysiologic understand of impairments to support
future scale up
a) Neural
b) Metabolic
4)Summary and next steps
Summary
 VML injury is a complex problem that has pathologic implications on the
muscle remaining and not just the area of muscle lost
 Function and physiologic understanding across the translational pipeline is
key to progress
Functional Recovery of the Musculoskeletal System Following Injury - Leveraging the Large Animal Model
Summary
 VML injury is a complex problem that has pathologic implications on the
muscle remaining and not just the area of muscle lost
 Function and physiologic understanding across the translational pipeline is
key to progress
Importance and Future Work
 The complexity will require a multi-disciplinary approach that should first
correct the physiology of the muscle
 Need to investigate how to promote a regenerative permissive
environment that balances physiology and improvements in function
 Evaluate optimal timing and duration of treatments alone or combined with
regenerative medicine approaches in efforts to improve long term function
 Novel approaches that can fill the unmet need
Collaborators
Jarrod Call, PhD - University of Georgia
Benjamin Corona, MD PhD - Wake Forest University
Dan Garry, MD PhD – University of Minnesota
Mary Garry, PhD – University of Minnesota
Jessica Rivera, MD PhD – Louisiana State University
Gordon Warren, PhD - Georgia State University
Fibralign Corp.
Michael Paukshto, PhD
Tatiana Zaitseva, PhD
Lab: http://smprl.umn.edu/
@GreisingLab
Current Lab Members
Shefali Bijwadia
Angela Bruzina
Braydon Crum
Daniel Hoffman
Mason Lentz
Thomas Lillquist
Peter Nicholson
Emma Pritchard
Christiana Raymond-Pope, PhD
Past Lab Members (Graduates)
Alec Basten (BS, MS)
Rachael Bloxzom (BS)
Kyle Dalske (MS)
Amanda Russell (BS)
Jacob Sorensen, PhD
Matt Borkowski
Chris Rand
Sydney Mensen
Thank you for participating!
CLICK HERE to learn more and
watch the webinar

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Functional Recovery of the Musculoskeletal System Following Injury - Leveraging the Large Animal Model

  • 1. Copyright 2022. All Rights Reserved. Contact Presenter for Permission Functional Recovery of the Musculoskeletal System Following Injury – Leveraging the Large Animal Model Sarah Greising, PhD Kinesiology University of Minnesota Associate Professor
  • 2. Functional Recovery of the Musculoskeletal System Following Injury - Leveraging the Large Animal Model Sarah Greising, PhD Associate Professor Henry L. Taylor-Arthur S. Leon Professorship grei0064@umn.edu 08. December. 2022
  • 3. Skeletal muscle function and physiology Limited regenerative potential of skeletal muscle VML injury Small to large animal models Functional recovery
  • 4. Grogan & Hsu, J Am Acad Orthop Surg 2011
  • 5. Injury in which a critical portion of a muscle or muscle unit is abruptly removed due to trauma or surgery Outcomes associated with VML injury • Persistent functional deficits • Loss of range of motion • Chronic disability Gentile et al., 2014 Garg et al., J Ortho Res 2015 Irrecoverable loss of contractile tissue and strength No current clinical, surgical, or rehabilitative standard of care that address the loss of endogenous material necessary for muscle regeneration or directly impact the soft tissue
  • 6. Loss of Strength Shift of Angle of Peak Torque “Longer Muscle Length” Loss of Active Range of Motion Garg et al., J Ortho Res 2015 Biodex Isokinetic testing 60˚/s; 10 Work Loops; Start at 0˚ - End active range of plantarflexion
  • 7. • Military trauma On an annual basis VML can result secondary to: • 150,000 open fractures • 36,000 industrial or farm accidents • 30,000 gunshot wounds and related trauma • 80 shark attacks • 13,000 soft-tissue cancers • 4,000 cleft lip and palate Trauma Physiologic
  • 8. Orthopaedic Trauma US economic burden to trauma is in excess of $400 billion yearly Soft tissue trauma • 2 million hospitalizations • 9 million bed days • 6.5 million outpatient visits • 18 million emergency room visits • 64 million physician's office visits US Department of Defense • $42.2 billion in initial care • $108.8 billion in lifetime disability benefit cost to injured service members
  • 9. The outcomes of these various forms of orthopaedic injuries is chronic disability in which muscle regeneration is not possible 1) Surgical, regenerative medicine, and/or rehabilitation approach targeted at regenerating the lost muscle 2) Approaches to improve the remaining muscle and prevent further degradation, i.e., remodel and/or adapt to the new cellular condition 3) Understand the pathophysiology of the both the injury and muscle remaining 4) How to improve function, i.e., functional recovery, chronically after injury
  • 10. Various models in literature • Abdominal wall, latissimus dorsi, tibialsis anterior, quadriceps, posterior compartment muscles • 10-50% of the muscle volume with functional deficits exceeding the volume lost Southern et al., Sci Rep 2019 Small & Large Animal Model of VML Injury
  • 11. Small & Large Animal Model of VML Injury Porcine peroneus tertius muscle (~5 g; 20% volume) Mouse & rat tibialis anterior (TA) muscle Mouse gastrocnemius, soleus, & plantaris muscles Pollet & Corona, MMB 2016 & Greising et al., Sci Rep 2017
  • 12. Chronic functional impairment Long-term dysfunction, reduced mobility and physical activity, co-morbidities, delayed amputation Chronic loss of skeletal muscle Pathophysiology Clinical Distinction Irrecoverable Volumetric muscle loss injury Lack of endogenous regenerative ability Increased pathologic fibrosis Chronic and heightened inflammation Altered muscle architecture/force transmission Chronic neural dysfunction Metabolic maladaptivity Satellite cell dysfunction Clinical Outcomes Inability to respond to rehabilitation
  • 14. Corona et al., JoVE 2021
  • 15. Pollet & Corona, MMB 2016 Corona et al., JoVE 2021
  • 16. Corona et al., JoVE 2021 Length control
  • 17. Corona et al., JoVE 2021
  • 18. Chronic functional impairment Long-term dysfunction, reduced mobility and physical activity, co-morbidities, delayed amputation Chronic loss of skeletal muscle Pathophysiology Clinical Distinction Irrecoverable Volumetric muscle loss injury Lack of endogenous regenerative ability Increased pathologic fibrosis Chronic and heightened inflammation Altered muscle architecture/force transmission Chronic neural dysfunction Metabolic maladaptivity Satellite cell dysfunction Clinical Outcomes Inability to respond to rehabilitation
  • 19. 1) Simple example of scale up with a HGF loaded biomaterial 2) Complex approach of scale up with pharmacologic treatment of fibrosis 3) Pathophysiologic understand of impairments to support future scale up a) Neural b) Metabolic 4) Summary and next steps
  • 21. Increased pathologic fibrosis An overaccumulation of extracellular matrix deposition during the repair process Impaired healing and regeneration
  • 22. Greising et al., BMC Musc 2018 Mouse VML model  2 Fold increase in passive torque  1-2 Fold increase in collagen content  Indicating increased stiffness
  • 23. Hoffman et al., Con Tiss Res 2021  Increased fibrosis and denser collagen in the muscle remaining  Suggesting increased stiffness
  • 24.  Conserved increase in collagen content between the rodent and pig  Suggesting increased stiffness Corona et al., Tis Eng A 2020
  • 25. Awasthi et al., Onco Targets Therp 2015 Anti-Fibrotic Treatment Nintedanib Intracellular tyrosine kinase inhibitor that targets fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor receptor (PDGFR) α/β, vascular endothelial growth factor receptor (VEGFR) 1-3, and the Src family of tyrosine kinases Lck, Lyn, and Flt-3 I n j u r y N a i v e C o n t r o l V M L A l o n e V M L + N i n t e d a n i b 0 200 400 600 800 Peak Torque (mN*m/kg) Mouse VML model
  • 26. Awasthi et al., Onco Targets Therp 2015 Anti-Fibrotic Treatment Nintedanib Intracellular tyrosine kinase inhibitor that targets fibroblast growth factor receptor (FGFR) 1-4, platelet-derived growth factor receptor (PDGFR) α/β, vascular endothelial growth factor receptor (VEGFR) 1-3, and the Src family of tyrosine kinases Lck, Lyn, and Flt-3 Pig VML model Corona et al., Tis Eng A 2020
  • 27.  Anti-fibrotic treatment diminished the VML- induced change in stiffness  Non-repaired and non-treated VML muscle have a 4-7 fold increase in stiffness 1-month post-injury Superficial Deep Corona et al., Tis Eng A 2020
  • 28.  Greater force deficit in the anti-fibrotic treated group than the VML non-repaired, non- treated  One-month post-VML there is a similar deficit of ~35% when normalized for muscle size Corona et al., Tis Eng A 2020
  • 29.  Preservation of directionality of the natural wound healing response  In many genes, the anti-fibrotic treatment following VML injury consistently affected expression by attenuating the magnitude of upregulation  As opposed to completely inhibiting upregulation (or downregulating) Corona et al., Tis Eng A 2020 Fibrosis Wound healing
  • 30. Increased pathologic fibrosis An overaccumulation of extracellular matrix deposition during the repair process Impaired healing and regeneration How do we optimize treatment delivery or timing? Keep this TGFβ independent? How to integrate with other approaches?
  • 31. Chronic neural dysfunction Full maturation of regenerated or repaired muscle fibers is dependent on fiber innervation
  • 32. Laminin/Neurofilament persistent functional deficits maintained descending axons maintained α-motor neurons, but persistent axotomy Corona et al., Mus Nerv 2018  Retained but limited capacity for reinnervation
  • 33. Pig VML model  No motor neuron death, but significant axotomy  Notably, motor neurons have retained capacity for reinnervation maintained α-motor neurons  Retained but limited capacity for reinnervation
  • 34. Nuclei (DAPI) / Axons (2H3-SV2 & S100) / NMJ αBTX  What about innervation at the fibers?
  • 35. Sorensen et al., J Appl Phys 2021 Secondary enervation and the chronic appearance of sprouting and poly-innervation are part of the sequela of injury Contribute to the chronic loss of muscle function post-VML injuries The maintenance of NMJ size and complexity indicate the potential for NMJs to be reinnervated, supportive to retention of motor neurons Pre-synaptic (2H3-SV2) / Post-synaptic (αBTX)
  • 36. Post-synaptic NMJ (αBTX) / Axons Pre-synaptic (2H3-SV2) / Nuclei (DAPI) / S100 tSC co-localization What about the specialized terminal Schwann cell (tSC)?
  • 37. Post-synaptic NMJ (αBTX) / Axons Pre-synaptic (2H3-SV2) / Nuclei (DAPI) / S100 (tSC co- localization) Hoffman et al., In Review Delayed increase in tSC number Possible pathologic trophic activity
  • 38. Can the potential to reinnervate be targeted? Herceptin: Monoclonal Antibody designed to target the ErbB2/HER2 receptor in Breast cancer cells. In skeletal muscle Neuregulin activates the ErbB/HER receptors for downstream activation of nerve development and other cellular processes Has shown a paradoxical role in promoting axon outgrowth following inhibition Sorensen et al., In Review
  • 39.  No functional improvement  Able to mitigate secondary denervation and pathologic NMJ characteristics Sorensen et al., In Review  Although paradoxical, inhibiting the ErbB2 receptor chronically
  • 40. Chronic neural dysfunction  Prolonged motor neuron axotomy and secondary denervation may have considerable impact on the functional capacity  Optimistically, there is a lot of remaining potential  How do we optimize treatment delivery or timing?  How do we optimize the development of regenerative medicine approaches to support reinnervation, considering an overactive local environment?  Understand and target supporting aspects of the NMJ like the tSCs, along with all the other aspects (e.g., satellite cells, FAPS, growth factors, immune cells) is important to support ongoing potential for stabilization and reinnervation in efforts to support long-term functional recovery
  • 41. Metabolic maladaptively Lack of standard metabolic response locally Whole-body implications
  • 42. Acute and local destruction of the mitochondrial network that corresponds to mitochondrial dysfunction Southern et al., Sci Rep 2019
  • 43. Distance from Injury Site Southern et al., Sci Rep 2019
  • 44. Greising et al., BMC Muscul Dis 2018 Southern et al., Sci Rep 2019 Injury-induced increase in mitochondrial content in the remaining muscle, but they have a reduced oxidative capacity both acutely and chronically S h a m VM L 0 1 2 3 4 C S (n m o l/s /m l) * S h a m VM L 0 .0 0 .2 0 .4 0 .6 F IS 1 /G A P D H ( r .l.u .) * * Chao et al., J Appl Phys 2019 Pig VML model Mouse VML model
  • 45. Mitochondrial respiration states are impaired across the respiratory states chronically McFaline-Figueroa et al, Tis Eng A 2022
  • 46. Electron conductance is slowed in VML- injured muscle compared to injury naïve muscle and this is associated with a greater mitochondrial membrane potential Impaired carbohydrate lipid oxidation oxygen consumption (JO2) at different ATP Gibb’s free energy states for carb vs. fat substrate McFaline-Figueroa et al, In Review
  • 47. Dalske et al., PLOS 2021 Injury-induced impairment in whole-body metabolism M o re lip id s M o re c a r b s
  • 48. Decreased carbohydrate oxidation and increased lipid oxidation Due primarily to changes in substrate oxidation and fuel selection N a i v e V M L 0 .0 0 0 .0 5 0 .1 0 0 .1 5 d e lta R E R * 0 .7 0 .8 0 .9 1 .0 R E R N aive V M L M o re lip id s M o re c a r b s A c tiv e P h a s e In a c tiv e P h a s e Raymond-Pope et al., In Review
  • 49. Metabolic maladaptively Reduced mitochondrial function and enzymatic activity Chronic metabolic rate and RER reductions with no change in activity Can we optimize a treatment? How to correct mitochondrial function for long term health? How to integrate with other approaches?
  • 50. 1) Simple example of scale up with a HGF loaded biomaterial 2) Complex approach of scale up with pharmacologic treatment of fibrosis 3) Pathophysiologic understand of impairments to support future scale up a) Neural b) Metabolic 4)Summary and next steps
  • 51. Summary  VML injury is a complex problem that has pathologic implications on the muscle remaining and not just the area of muscle lost  Function and physiologic understanding across the translational pipeline is key to progress
  • 53. Summary  VML injury is a complex problem that has pathologic implications on the muscle remaining and not just the area of muscle lost  Function and physiologic understanding across the translational pipeline is key to progress Importance and Future Work  The complexity will require a multi-disciplinary approach that should first correct the physiology of the muscle  Need to investigate how to promote a regenerative permissive environment that balances physiology and improvements in function  Evaluate optimal timing and duration of treatments alone or combined with regenerative medicine approaches in efforts to improve long term function  Novel approaches that can fill the unmet need
  • 54. Collaborators Jarrod Call, PhD - University of Georgia Benjamin Corona, MD PhD - Wake Forest University Dan Garry, MD PhD – University of Minnesota Mary Garry, PhD – University of Minnesota Jessica Rivera, MD PhD – Louisiana State University Gordon Warren, PhD - Georgia State University Fibralign Corp. Michael Paukshto, PhD Tatiana Zaitseva, PhD Lab: http://smprl.umn.edu/ @GreisingLab Current Lab Members Shefali Bijwadia Angela Bruzina Braydon Crum Daniel Hoffman Mason Lentz Thomas Lillquist Peter Nicholson Emma Pritchard Christiana Raymond-Pope, PhD Past Lab Members (Graduates) Alec Basten (BS, MS) Rachael Bloxzom (BS) Kyle Dalske (MS) Amanda Russell (BS) Jacob Sorensen, PhD Matt Borkowski Chris Rand Sydney Mensen
  • 55. Thank you for participating! CLICK HERE to learn more and watch the webinar