Human skeletal muscle cytosols are refractory to cytochrome c-dependent activation of type-II caspases and lack

D H Burgess1, M Svensson, T Dandrea

  • 1Institute of Environmental Medicine, Karolinska Institute, Box 210, S-17177 Stockholm, Sweden.

Insights

Human skeletal muscle cells resist apoptosis via a cytochrome c pathway due to lacking Apoptosis Protease Activator Factor-1 (APAF-1). This prevents mitochondrial-mediated cell death, potentially an evolutionary survival adaptation.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Physiology

Background:

  • Apoptotic regulatory mechanisms in skeletal muscle remain unclear.
  • Apoptotic events are observed after exercise, muscle injury, and in dystrophinopathies.
  • The role of cytochrome c in muscle apoptosis is under investigation.

Purpose of the Study:

  • To investigate the presence and functionality of the cytochrome c-mediated apoptotic pathway in human skeletal muscle.
  • To determine if skeletal muscle cells possess the necessary components for mitochondrial-mediated apoptosis.

Main Methods:

  • Analysis of skeletal muscle cytosols from healthy human volunteers.
  • Assay of caspase activation in response to cytochrome c and dATP.
  • Assessment of Apoptosis Protease Activator Factor-1 (APAF-1) at protein and mRNA levels.

Main Results:

  • Skeletal muscle cytosols lack the ability to activate type-II caspases via a cytochrome c pathway, despite containing procaspase-3 and -9.
  • The absence of an endogenous inhibitor was confirmed; muscle cytosols enhanced control caspase activity.
  • Apoptosis Protease Activator Factor-1 (APAF-1) was absent in muscle cytosols at both protein and mRNA levels.

Conclusions:

  • Human skeletal muscle cells are refractory to mitochondrial-mediated apoptotic events.
  • Skeletal muscle evades a major pro-apoptotic regulatory mechanism.
  • This refractoriness may be an evolutionary adaptation for cell survival, supporting energy generation for motility.

Related Concept Videos

Studying the Cytoskeleton01:17

Studying the Cytoskeleton

The cytoskeletal architecture can be studied using different microscopic and biochemical techniques. Electron microscopy was instrumental in discovering the cytoskeletal architecture around the 1960s, which allowed obtaining structural information at a high-resolution level. However, the sample preparation procedure often limits this ability in biological samples. Several protocols have been developed over the years to optimize sample preparation. In one of the protocols known as rotary...
Caspases01:24

Caspases

Caspase, a family of cysteine proteases, serve as effectors in apoptosis. The ced3 gene in C.elegans was first identified to be involved in apoptosis. This gene encodes the ced-3 caspase that is similar to the interleukin-1-beta converting enzyme or ICE in mammals. In addition to apoptosis, caspases also function in the inflammatory response. Inflammatory caspases are essential in activating pro-inflammatory cytokines that recruit immune cells and block the replication of pathogens inside cells.
The Intrinsic Apoptotic Pathway01:31

The Intrinsic Apoptotic Pathway

Internal cellular stress, such as cellular injury or hypoxia, triggers intrinsic apoptosis. The B-cell lymphoma 2 (Bcl-2) family of proteins are the primary regulators of the intrinsic apoptotic pathway. For example, during DNA damage, checkpoint proteins, such as Ataxia Telangiectasia Mutated (ATM protein) and Checkpoints Factor-2 (Chk2) proteins, are activated. These proteins phosphorylate p53 which further activates pro-apoptotic proteins, such as Bax, Bak, PUMA, and Noxa, and inhibits...
Overview of Skeletal Muscle01:15

Overview of Skeletal Muscle

Skeletal muscles are composed of a bundle of muscle fibers and are attached to bones through tendons. Each skeletal muscle fiber is a single muscle cell. The sarcolemma, the plasma membrane of a skeletal muscle cell, consists of a lipid bilayer and glycocalyx that supports muscle fibers. The sarcolemma extends into the muscle cells to form tubular structures called transverse or T-tubules. Each side of the T-tubules consists of a membrane-bound structure called the sarcoplasmic reticulum,...
Satellite Stem Cells and Muscular Dystrophy01:21

Satellite Stem Cells and Muscular Dystrophy

Satellite stem cells or myosatellite cells are quiescent stem cells that Alexander Mauro first identified in 1961. These cells are located between the sarcolemma, the plasma membrane of muscle fibers, and the basal lamina, the connective tissue sheath covering it. These mononucleated cells are activated in response to muscle injury, can transform into myoblasts, and may form or repair muscle fibers. Myosatellite cells can provide additional myonuclei for muscle regeneration or return to a...
Microscopic Anatomy of Skeletal Muscles01:13

Microscopic Anatomy of Skeletal Muscles

Skeletal muscle cells, also called muscle fibers, are distinctly elongated, multi-nucleated, slender biological units. They are packed with specialized structures designed to facilitate their primary function, which is contraction.
The muscle sarcolemma is a plasma membrane enclosing each muscle cell that conducts electrical signals called action potentials. The sarcolemma extends into the cell to form T-tubules, ensuring the neural impulses are uniformly distributed across the entire muscle...