Lecture 28 - Muscle regeneration

Question 1

The first event, following injury, is muscle _______and ________, which occurs within the first minutes and continues for up to ____to ____weeks after injury. Muscle regeneration begins _______________________ and peaks at about ____days post-injury. Fibrosis usually occurs at ___ ____ post-injury and increases over time for up to ___ weeks post-injury

Answer 1

The first event, following injury, is muscle degeneration and inflammation, which occurs within the first minutes and continues for up to one to two weeks after injury. Muscle regeneration begins in the first week post-injury and peaks at about 14 days post-injury. Fibrosis usually occurs at two weeks post-injury and increases over time for up to four weeks post-injury

Question 2

What are the events leading to muscle fibre degeneration?

Answer 2

autolysis - activaiton of intracellular degradative enzymes (proteases and phospholipases)

an inflammatory response

• commmitment of phagocytic inflammatory cells
• localised neutrophils (realease degradative enzymes, destroy debris, incease vascular permeability)
• stimulate monocyte accumulation and satellite cells
• critical for initiating muscle fibre repair
• accumulated macrophages

Question 3

What affects the usefulness of inflammation?

Answer 3

affected by viability of local vasculature

inflammatory response is critical for msucle fibre regeneration

too little, too much, too short or too long inflammation can all interfere with optimal regeneration

Question 4

True or false

Ageing prolongs inflammatory marker expression in regenerating rat skeletal muscles after injury

Answer 4

true

Question 5

Myoblasts derived from the satellite cells fuse together to form…

Answer 5

myotubes with a maturity gradient

regenerated mscule fibre, with a new satellite cell and centrally located myonuclei

Question 6

_______enables the new fibre to grow and mature and replaces the damaged portion of the fibre

Answer 6

Myofilbrillogenesis

Question 7

Where possible regeneration is guided by extracellular structures

if the basal lamina is damaged…

Answer 7

myotube formation is impaired

e.g with a crushed limb, lacerations etc…

Question 8

What is the concept of a ‘‘maturity gradient’’?

Answer 8

myotube formation/fibre maturation follows a maturity gradient

most advanced at surviving fibre stumps, less mature at centre of injury

internal re-organisation and MPS forms new fibres

maturation of protein isoforms

synthesis of new basal lamina

note: central nucleation during myotube formation as sign of early regeneration

Question 9

Kinetics and amplitude of each regenerative phase may vary depending on:

Answer 9

extent of injury, the number of cells to replace

the muscle injured

the animal model

• species differences
• metabolic rate

differential expression of transcription factors, myogenic regulatory factors and growth factors

other influences:

• ongoing injury/re-injury
• vascular supply
• inflammatory signature
• host (systemic) environment (young vs. Old)
• Neural function
• genetic influences

Question 10

Chronological age alone is not a factor that limits the…

Answer 10

intrinsic ability of a msucle to regenerate

Question 11

What is poor regeneration of muscle in old animals a function of?

Answer 11

the environment for regeneration provided by the old host

Question 12

With ageing there is reduced:

Answer 12

physical activity (exercise)

trophic support: growth hormone (GH) and growth factors (e.g FGF, IGF)

neural support

Question 13

True or False

shared circulation restored satellite cell activity in aged mice

Answer 13

true

circulating factors are important in muscle regeneration, not just factors intrinsic to muscle

Question 14

Deficiency in _______ with increasing age contributes to the poor regeneration of muscles in old animals

Answer 14

reinnervation

Question 15

True or false

Newly regenerated fibres in msucle of young and old animals are less resistant to injury

Answer 15

False

they are more resistant

maintenance of newly regenerated fibres by conditioning may prevent inadvertent damage, particularly in muscle of elderly people

Question 16

What are changes in type of Myosin heavy chain folloing injury of a rat (soleus) slow twitch muscle?

Answer 16

less type 1 MyHC and more Type 11a fibres

Question 17

How can growth factors enhance muscle repair after injury?

Answer 17

GF (e.g IGF-1) can improve muscle regeneration, but the post-injury healing process remains incomplete

the use of anti-fibrotic agnets that antagonise the effect of TGF-beta1 can prevent fibrosis and improve muscle healing and recovery

Question 18

optimal muscle recovery may require the use of novel technologies, such as:

Answer 18

cell therapy, gene therapy and tissue engineering.

needed to achieve high levels and long-term persistence of these GFs and cytokines within the muscle

Question 19

So what are the ways we can interfere and promote healthy muscle regeneration?

Answer 19

artificial bioscaffolds or substrates for aiding fibre formation

satellite cell activators

cell therapies

anti-infammatory agents

growth factors and anaboic agnets

anti-fibrotic agents

angiogenic promoters and blood flow modulators - enhancing blood supply can enhance regenerative response