(a) Name the proteins and their functions involved in skeletal muscle contraction. Unlike skeletal muscles, why do cardiac…

(a) Skeletal muscle proteins, and why cardiac muscle does not fatigue (20 marks)

Proteins of skeletal muscle contraction.

• Contractile: actin, forming the thin filament as a double helix of F-actin, binds the myosin head. Myosin, forming the thick filament, has a tail (light meromyosin) that builds the filament and a head (heavy meromyosin) with ATPase activity that binds actin and pulls it in the power stroke.
• Regulatory: tropomyosin lies along actin and covers the myosin-binding sites at rest. The troponin complex is made of TnT (binds tropomyosin), TnC (binds Ca²⁺) and TnI (inhibits actin–myosin interaction), and Ca²⁺ binding to TnC moves tropomyosin and switches contraction on.
• Structural: titin is an elastic protein anchoring the thick filament to the Z disc and returning the sarcomere to length after stretch. Nebulin sets thin-filament length, α-actinin cross-links actin at the Z disc, myomesin holds the thick filaments at the M line, desmin links adjacent Z discs, and dystrophin links actin to the sarcolemma (its absence causes Duchenne muscular dystrophy).

Why cardiac muscle does not fatigue.

• It is entirely aerobic. Mitochondria take up about a third of the cell volume, and myoglobin is abundant, so ATP is made continuously by oxidative phosphorylation and there is no build-up of lactic acid.
• It has a very rich blood supply, with a capillary for each fibre, and it extracts about 70–75% of the oxygen from blood. It also uses fatty acids, glucose and lactate as fuels.
• Its action potential has a long plateau, so the refractory period (about 250 ms) lasts almost the whole of contraction. It cannot be tetanised, so the heart always relaxes between beats, and the rest during diastole restores perfusion (coronary flow is mainly in diastole).
• The intrinsic pacemaker (SA node) sets a regular rhythm, and intercalated discs and gap junctions make it work as a syncytium.

In skeletal muscle, sustained or intense contraction outstrips the oxygen supply, so it depends on anaerobic glycolysis and fatigues.

(b) Generation, differentiation and activation of T cells (15 marks)

Generation. T-cell precursors arise from haematopoietic stem cells in the bone marrow, pass through common lymphoid progenitors and travel in the blood to the thymus, where they enter as thymocytes.

Differentiation in the thymus.

• Double negative (CD4⁻CD8⁻): the TCR β chain gene is rearranged by V(D)J recombination (RAG1 and RAG2), and pairs with the pre-Tα chain as the pre-TCR. Cells that pass this test (β-selection) proliferate.
• Double positive (CD4⁺CD8⁺): the α chain is rearranged, producing an αβ TCR.
• Positive selection in the cortex: cortical epithelial cells present self peptide–MHC. Cells whose TCR binds self-MHC with moderate affinity survive, and the rest die by neglect. Binding to MHC I gives CD8⁺ cells, and to MHC II gives CD4⁺ cells (single positive).
• Negative selection in the medulla: cells that bind self antigens strongly (with tissue antigens shown by AIRE) undergo apoptosis (central tolerance), and some become regulatory T cells. About 95% of thymocytes die. Mature naive T cells leave for the lymph nodes and spleen.

Activation in the periphery. An antigen-presenting cell (dendritic cell) gives three signals.

• Signal 1: the TCR recognises the peptide–MHC, helped by CD4 or CD8.
• Signal 2: co-stimulation, by CD28 on the T cell binding B7 (CD80/86). Without it, the cell becomes anergic.
• Signal 3: cytokines direct differentiation: IL-12 to Th1, IL-4 to Th2, TGF-β with IL-6 to Th17, TGF-β to Treg, and IL-21 to Tfh.

The activated cells make IL-2 and expand clonally into effector subsets (helper Th1, Th2, Th17, Tfh and Treg, and cytotoxic CD8⁺ cells that kill with perforin and granzymes) and memory cells.

(c) Teratogenesis and how teratogens interfere with early development (15 marks)

Definition. Teratogenesis is the production of congenital malformations by an agent (a teratogen) that disturbs normal embryonic development.

Agents and defects.

• Drugs: thalidomide (limb defects, phocomelia), isotretinoin (retinoic acid; craniofacial and heart defects), valproate (neural tube defects) and warfarin.
• Infections: rubella (cataract, deafness and heart defects), Zika virus (microcephaly), cytomegalovirus and Toxoplasma.
• Chemicals: alcohol (fetal alcohol syndrome), methylmercury, and lead.
• Radiation: ionising radiation (microcephaly).
• Maternal conditions: diabetes (heart defects, caudal regression) and folate deficiency (neural tube defects).

Mechanisms. Teratogens may damage DNA (mutagenesis), kill cells (excess apoptosis), block cell division, migration or differentiation, or disturb signalling and gene expression. Excess retinoic acid upsets Hox gene patterning, thalidomide marks the transcription factor SALL4 for degradation, alcohol kills neural crest cells, and folate antagonists impair DNA synthesis and neural tube closure.

Principles.

• Critical period: sensitivity is greatest during organogenesis (weeks 3–8 in humans), when heart, brain and limbs form. In the first two weeks the effect is all-or-none (death or complete repair), and later exposure causes growth or functional defects.
• Dose: there is a threshold below which no effect is seen, and the severity rises with dose.
• Susceptibility depends on the genotypes of the mother and embryo, and on transfer across the placenta.