Development of Skeletal Muscle

Skeletal Muscle Development

  • Skeletal muscle development is illustrated with images of muscles in the upper limb and abdomen.

Somite Development

  • Paraxial mesoderm, located near the neural tube, gives rise to somites. These somites develop into:
    • Myotome (muscles of the back, limbs, and ribs)
    • Dermatome (dermis of the back)
    • Sclerotome (vertebrae and rib cartilage)
  • Past research demonstrates cell-cell communication influences differentiation.
  • Experiment:
    • Young somites cultured alone $\rightarrow$ mesenchymal cells.
    • Somites cultured with notochord $\rightarrow$ cartilage.
    • Somites cultured with the ventral neural tube $\rightarrow$ cartilage.
    • Somites cultured with the dorsal part of the neural tube $\rightarrow$ striated muscle.
  • Myotomes form muscles of the neck and trunk.
  • Myoblasts migrate laterally from the somites to form limb muscles.
  • Myoblasts migrate from the myotome to form:
    • Epimere: Muscles of the back
    • Hypomere: Muscles of the thorax and abdomen
  • Myotomes differentiate into:
    • Occipital myotomes
    • Cervical myotomes
    • Thoracic myotomes
    • Lumbar myotomes
    • Sacral myotomes
    • Regressing caudal myotomes
    • Primordia of the eye muscle

Myoblast Fusion

  • Myoblasts undergo frequent divisions and coalesce to form multinucleated syncytial muscle fibers (myotubes).
  • Skeletal muscle cells are multinucleated with peripheral nuclei.
  • Experiment illustrating myoblast fusion:
    • Isolated myoblasts in culture (stained with green fluorescent protein and myosin).
    • Myoblasts differentiate and fuse, producing myosin.
    • Fused structures form striated muscle fibers with peripheral nuclei.

Myotube Formation

  • Mesenchymal cells (myoblasts) move and join to form myotubes.
  • Developing muscle cells form contractile filaments.
  • Accumulation of filaments generates striations.
  • Sarcomeres are the units forming striations in skeletal muscle.
  • Satellite cells are stem cells of skeletal muscle that aid in regeneration and repair.
  • Sarcomere Structure:
    • Myosin interacts with actin to form the contractile unit.
  • Rows of sarcomeres form myofibrils.
  • Muscle is composed of smaller, structured units.

Histology of Developing Skeletal Muscle

  • Striations are visible along the skeletal muscle (individual sarcomeres).
  • Nuclei are peripheral to the fibers.
  • Myofibrils are multinucleated and contain fused cells. High nutritive requirements leads to visible presence of blood vessel and red blood cell.

Muscle Development Events

  • Cells transition from undifferentiated state to terminally differentiated form:
    • Somites $\rightarrow$ Myogenic progenitor cells (myoblasts) $\rightarrow$ Myotube $\rightarrow$ Myofiber
  • Process involves determination, differentiation, and maturation regulated by molecular factors.
  • Activating factors (influenced by proximal tissues like neural tube and notochord):
    • Switch on MIF5 and PAX3 and proliferation factors.
  • Muscle-specific factors:
    • MyoD, myogenin.
  • Differentiation factors:
    • Switch on myotube genes and MRF4 to differentiate into mature myofibers.
  • The progression of tissue from undifferentiated to terminally differentiated form requires changes in gene expression.

Gene Knockout Studies

  • Gene knockout mice are used to study gene importance in development.
  • Absence of either MIF5 or MyoD alone does not prevent skeletal muscle formation due to redundancy.
  • Absence of both MIF5 and MyoD leads to muscle failure and is incompatible with life.

Regulation of Muscle Growth

  • Muscle growth is both positively and negatively regulated.
  • Positive regulators: MIF5, MyoD
  • Negative regulator: Myostatin (TGF beta family member).
  • Myostatin inhibits muscle growth to maintain normal size.
  • Belgian Blue bull has lower myostatin function, resulting in 40% increase in muscle mass.
  • German boy with a mutation in the myostatin gene exhibits extraordinary skeletal muscle development.
  • Myostatin regulates the development and growth of skeletal muscle; loss results in myostatin-related muscle hypertrophy.

Therapeutic Implications

  • Blocking myostatin may help with muscle wasting conditions like cachexia in cancer patients.
  • Myostatin blocking agents are marketed to bodybuilders.

Muscle Degeneration

  • Tissues can degenerate later in life, e.g., muscular dystrophy (Duchenne muscular dystrophy).
  • Absence of dystrophin makes muscle fibers more susceptible to damage.

Muscle Fiber Types

  • Muscles have different uses depending on their fiber types.
  • Slow Twitch Fibers:
    • Small, many mitochondria, lots of myoglobin.
    • Resistant to fatigue, generate less tension.
    • Used for maintaining posture, long contractions.
    • Example: Marathon runners.
  • Type II Fast Twitch Fibers:
    • Fast Oxidative:
      • Middle distance swimmers, middle distance runners.
      • Lots of mitochondria, lots of glycogen.
      • Can do anaerobic glycolysis, generate high peak muscle tension.
    • Fast Glycolytic:
      • Short distance sprinters, weightlifters.
      • Fewer mitochondria, lots of glycogen.
      • Fatigue rapidly, rapid contraction, precise movements.
  • Different fiber types develop from embryonic and fetal muscle cell precursors.
  • Adults retain plasticity due to satellite cells, which can form new muscle fibers.
  • Exercise can lead to hypertrophy and increased resistance to fatigue, underpinned by changes in gene expression.

Satellite Cells

  • Small cells close to muscle fibers within the basal lamina.
  • Involved in growth and are considered the resident stem cell population.
  • Regenerate muscle fibers and can proliferate and fuse to form new muscle fibers.
  • Important for muscle repair and regeneration.