Muscle Flashcards
Other then what the muscle looks like what is another assessment that deems the muscle fit?
Function
Name 3 ways of evaluating mdx mice for muscle potential?
Grip strength, vertical hang test and whole body functional tests
What are pros and cons of functionary assays in vitro?
Pros- Can assess functional parameters of muscle directly, free from influence of nerve or blood supply
Cons-Less physiological since nerve/blood supply are removed
What are the pros and cons of functional assays in situ?
Pros- preservation of nerve and blood supply, can assess properties of a single muscle
Cons-More technically challenging, time consuming
What are pros and cons of functional assays in Vivo?
Pros- minimally invasive, able to assess muscle groups
Cons-more technically difficult, expensive, cannot isolate effects to a specific muscle group
Overexpression of Hsp72 leads to what in dystrophic mice?
Decreased characteristics of muscular dystrophy- increased specific force of the muscle, decrease in collagen build up
What is force deficit a functional indicator of?
Muscle damage
What is the mechanical hypothesis of muscle fibre necrosis?
Loss of DGC leads to contraction-induced rupture of muscle cell membrane
Exercise in DND patients and mdx mice causes greater muscle damage than control
What is the calcium hypothesis of muscle fibre necrosis?
Influx of Ca into cytosine overwhelms muscle cells ability to maintain Ca levels
Elevated Ca concentration causes programmed cell death via activation of pro teases such as Calpains
What is the gene regulation hypothesis for muscle fibre necrosis?
Failure of certain molecules to be localised to the muscle membrane when DGC components are absent prevents proper signalling molecules from being recruited
What is the vascular hypothesis for muscle fibre necrosis?
Loss of sarcolemmal nNOS and reduced paracrine No signalling to the muscle leading to functional uncle ischaemia
Reduction of muscle ischemia may all of DMD/BMD patients to perform more work with less muscle injury therefore slowing disease progression
What is the inflammatory hypothesis for tissue remodelling?
Muscle in DMD exhibit component of chronic inflammatory response
Inflammation causes over expression of extra cellular matrix gees and contributes to fibrosis
What is the sequence of muscle injury and repair
Degeneration
Inflammation
Regeneration
Fibrosis
What is the key inflammatory response cells needed for successful regeneration?
Satellite cells
What is fibrosis?
Abnormal and chronic increase in extra cellular connective tissue that interferes with function
Replaces contractile material
Creates a physical barrier that limits efficacy of drugs
What are three possible therapies for the treatment of muscular dystrophy?
Gene therapies- correction of genetic defect
Cell therapies- stem cell therapies
Pharmacological therapies- prevention of secondary consequences of phenotypic defect
Name some contributing mechanisms to muscle breakdown in MD?
Calcium influx
Inflammatory response
Fibrosis
Oxidative stress
What are Corticosteroids and give an example?
Ex. Prednisone
Corticosteroids maintain or decrease muscle fibre size (less susceptible to trauma)
Used to counter effects of chronic inflammation and preserve existing muscle fibres
Delays needs for wheelchairs
What is the mechanism of action for Corticosteroids?
Slow the invasion of fibrotic tissue into the muscle
What are the side effects of corticosteroids?
Weight gain, fluid retention, high blood pressure
What is another option then Corticosteroids with minimal side effects
VBP15
What are muscle anabolic agents?
Make the muscles bigger and stronger
Increase muscle mass/protein synthesis and decrease muscle protein degradation
Ex. Anabolic steroids, growth hormones, growth factors (IGF-1)
What is Myostatin blockade?
Therapy for muscle wasting diseases
Genetic manipulation and neutralising antibodies
Results in increase mass and force output and decrease degeneration
What does myostatin do?
Blocks the processes of proliferation and differentiation of muscle growth
What is IGF-1?
Growth factor, important in normal muscle growth and repair
Levels of IGF are increased after injury and overload
Stimulates muscle cell differentiation
Increases muscle mass and strength
PROVIDE FAST to SLOW MUSCLE FIBRE TRANISITION
Decreases fibrosis
increased oxidative capacity of muscles
However, possible concerns with tumour growth
What are beta agonists?
Powerful anabolic effect on muscle
Have the potential to reverse muscle atrophy
Increases muscle mass ,fibre size, force capacity
CAUSE SLOW-FAST MUSCLE FIBRE TRANSITIONS
Enhance muscle repair
Describe Albuterol
It is a beta agonist that provided modest increases in strength with no side effects
A more efficacious beta agonist may be required where there is severe wasting and weakness-but need to limit cardiac effects
Name the 9 possible therapies for muscular dystrophy
Anabolic steroids B2 agonists IGF-1 Myostatin inhibitors Proteasome inhibitors Membrane sealants Vitamin E Ca channel blockers Heat shock protein (HSP72)
What is Interleukin 15 used for?
Possible treatment for muscle wasting disorders
It is a myokine that is released during muscle contractions
Increased glucose uptake and lowers rate of protein deterioration
May play a role in metabolic adaptation of muscle in response to physical activity
Decreases collagen infiltration in mdx diaphragm
What is Poloxamer-188?
Synthetic surfactant that is incorporated into cell membranes to ‘plug’ holes in torn membranes
What is SERCA?
Pump that pulls Ca back into sarcoplasmic reticulum
Dysfunction likely contributed to Ca overload in DMD
How can we preserve or improve SERCA pump function?
Heat Shock proteins
Describe the role of heat shock proteins
Involved in re-folding denatured proteins
Produced by all cells in response to stressors
How does Hsp72 help SERCA?
Protects against thermal inactivation and stabilises nucleotide domain
Improves Ca concentration through improvements in SERVA function under conditions of stress
What is BGP-15 and when does it work?
It is the pharmacological equivalent of Hsp72 in drug therapy form
Does not improve muscle function in an established dystrophic pathology but reduces fibrosis in TA
When does BGP-15 work/not work in dystrophic hearts?
Early stage BGP-15 treatment reduces fibrotic infiltration in the hearts of dystrophic mice
Later stage BGP-15 treatment reduces fibrotic infiltration in the hearts of dystrophic mice
Is there a therapeutic window of opportunity for DMD?
As soon as possible for greatest efficacy due to slow rate of pregression
What are some potential agents to reduce fibrosis in muscle?
TGF beta inhibitors
Tranilast- decreased fibrosis but did not improve specific force
What is a transcription promoter?
Drives expression of a gene of interest, provides control over expression
What are the 3 types of transcription promoters?
Constitutive- allows high expression of gene of interest
Tissue specific- gene only turned on in cells it can benefit
Inducible- control length of time the gene is expressed for
How much of the digerati skeletal muscle in DMD is needed to be corrected in order to observe an improvement in function and quality of life?
20% of muscle
Describe unencapsulated plasmid DNA delivery and other methods to aid in its efficacy
Safe, simple and cost effective method of gene delivery
Low efficacy
Better efficacy with a combination therapy approach with- protection from DNA degradation, combing with non-ionic carrier molecules, ultrasound and electro-oration
Pros- Able to deliver full length dystrophin gene
Cons- Low efficacy in absence of combination therapy, localised delivery only
What are the 2 methods of non-viral gene therapy?
Unencapsulated plasmid delivery and Dystophin restoration
What is a transcription promoter?
Drives expression of a gene of interest, provides control over expression
What are the 3 types of transcription promoters?
Constitutive- allows high expression of gene of interest
Tissue specific- gene only turned on in cells it can benefit
Inducible- control length of time the gene is expressed for
How much of the digerati skeletal muscle in DMD is needed to be corrected in order to observe an improvement in function and quality of life?
20% of muscle
Describe unencapsulated plasmid DNA delivery and other methods to aid in its efficacy
Safe, simple and cost effective method of gene delivery
Low efficacy
Better efficacy with a combination therapy approach with- protection from DNA degradation, combing with non-ionic carrier molecules, ultrasound and electro-oration
Pros- Able to deliver full length dystrophin gene
Cons- Low efficacy in absence of combination therapy, localised delivery only
What are the 2 methods of non-viral gene therapy?
Unencapsulated plasmid delivery and Dystophin restoration
