Musculoskeletal Physiology

Skeletal Muscle Microstructure

Skeletal muscle is organised hierarchically: the muscle belly is composed of fascicles → muscle fibres (individual multinucleated cells, 10–100 µm diameter, up to 30 cm long) → myofibrils (1–2 µm diameter, running the length of the fibre) → sarcomeres (the contractile unit, ~2.2 µm at rest, repeating in series).

The sarcomere is bounded by Z-discs (Z-lines), which anchor the thin filaments. The arrangement of thick and thin filaments creates the characteristic striated pattern visible under light microscopy: the A-band (dark) contains thick (myosin) filaments + overlapping thin (actin) filaments; the I-band (light) contains only thin (actin) filaments and bisects the Z-disc; the H-zone (central A-band, lighter) contains only thick filaments (no thin filament overlap); the M-line bisects the H-zone, linking myosin filaments. The A-band width remains constant during contraction; the I-band and H-zone narrow as thin filaments slide inward.

Thick filaments are composed of myosin II molecules (~300 per filament). Each myosin molecule is a hexamer: two heavy chains (forming a coiled-coil rod tail + two globular head domains) + two pairs of light chains per head. The myosin head is the molecular motor: it has an ATPase catalytic site and an actin-binding site. Thin filaments (~1 µm) are composed of: F-actin (double helix of G-actin monomers, each bearing a myosin-binding site); tropomyosin (coiled-coil protein running along the actin groove, sterically blocks myosin-binding sites at rest — each tropomyosin spans 7 actin monomers); troponin complex (TnT — anchors tropomyosin; TnI — inhibitory subunit, holds tropomyosin in blocking position; TnC — Ca²⁺-binding subunit, 4 Ca²⁺-binding sites, regulatory). Titin (connectin) is a giant elastic protein spanning from Z-disc to M-line; acts as a molecular spring, restoring sarcomere length after stretch and maintaining thick filament alignment.

Sliding Filament Theory and the Cross-Bridge Cycle

The sliding filament theory (Huxley, 1954) proposes that muscle shortening results not from filament shortening but from thin filaments sliding over thick filaments toward the M-line. This is powered by repetitive cycles of myosin head attachment, force generation, and detachment.

The cross-bridge cycle (ATP-dependent steps):

1. Resting state (rigor-like without ATP): myosin head tightly bound to actin in a post-power-stroke conformation.
2. ATP binding: ATP binds the myosin head → myosin-actin affinity decreases → myosin head detaches from actin.
3. ATP hydrolysis (cocking): ATP → ADP + Pi on the myosin head → myosin head cocked into the pre-power-stroke (high-energy) conformation (~90°).
4. Actin binding (weak binding): cocked myosin head weakly attaches to the next actin monomer along the thin filament (5–7 nm closer to the M-line).
5. Power stroke (force generation): Pi release → conformational change → myosin head rotates ~45° → thin filament moves ~5–10 nm toward the M-line. ADP still bound. Force generated.
6. ADP release: ADP released → myosin locked in rigor conformation on actin (post-power-stroke state). Return to step 1.

Each cross-bridge cycle consumes 1 ATP and generates ~3–4 pN of force and ~5–10 nm of displacement.

Excitation-Contraction (EC) Coupling

EC coupling links the action potential (electrical signal at the sarcolemma) to Ca²⁺ release (triggering contraction):

1. Motor neuron action potential → ACh released at NMJ → nicotinic AChR (ligand-gated Na⁺/K⁺) → end-plate potential → action potential in sarcolemma.
2. Action potential propagates along the sarcolemma and down T-tubules (transverse tubules — invaginations ensuring rapid and synchronous activation).
3. Dihydropyridine receptors (DHPRs) in the T-tubule membrane act as voltage sensors → conformational change mechanically activates ryanodine receptors type 1 (RyR1) on the adjacent sarcoplasmic reticulum (SR) terminal cisternae → RyR1 opens → Ca²⁺ flood from SR into cytoplasm.
4. Cytoplasmic Ca²⁺ rises from ~100 nM to ~10 µM: Ca²⁺ binds TnC → TnI releases → tropomyosin shifts ~7° → myosin-binding sites exposed → cross-bridge cycling begins.
5. Relaxation: SERCA (SR Ca²⁺-ATPase, ATP-dependent) pumps Ca²⁺ back into SR → cytoplasmic Ca²⁺ falls → TnC releases Ca²⁺ → TnI re-inhibits → tropomyosin re-blocks → relaxation.

Muscle Fibre Types

Skeletal muscle fibres are classified by myosin heavy chain (MHC) isoform and metabolic profile: Type I (slow-oxidative, MHC-I): red, fatigue-resistant, high mitochondrial density, aerobic, slow contraction, small motor units, used for sustained posture and endurance activity. Recruited first per Henneman's size principle (smallest motor units have lowest threshold). Type IIa (fast oxidative-glycolytic, MHC-IIa): intermediate in all properties; mixed aerobic/anaerobic. Type IIx (fast glycolytic, MHC-IIx): white, rapid fatigue, anaerobic glycolysis, large motor units, recruited last — used for explosive power and sprinting. Fibre type is determined by motor neuron type and is malleable with training.

Bone Physiology

Bone is a dynamic connective tissue with structural, metabolic (mineral reservoir — 99% of body Ca²⁺, 85% of phosphorus), and haematopoietic functions. Bone matrix: ~35% organic (type I collagen — tensile strength; osteocalcin; osteopontin) + ~65% inorganic (hydroxyapatite Ca₁₀(PO₄)₆(OH)₂ — compressive strength).

Bone cells: Osteoblasts (mesenchymal origin): synthesise osteoid → mineralisation; express RANKL and OPG. Embedded osteoblasts → osteocytes (mechanosensors via canalicular network; produce sclerostin under unloading → inhibits Wnt → suppresses osteoblast activity). Osteoclasts (haematopoietic, monocyte/macrophage origin): multinucleated; form sealed resorption lacuna (Howship's); H⁺-ATPase dissolves mineral; cathepsin K/MMP-9 digest collagen.

RANK/RANKL/OPG axis: Osteoblasts express RANKL → binds RANK on osteoclast precursors → osteoclastogenesis (NF-κB/NFATc1). OPG (osteoblast-secreted decoy receptor) binds RANKL → blocks RANK → inhibits osteoclasts. Oestrogen: ↑ OPG, ↓ RANKL → anti-resorptive. Denosumab: monoclonal anti-RANKL antibody (osteoporosis treatment). Bisphosphonates: inhibit FPPS in osteoclasts → impair GTPase prenylation → osteoclast apoptosis.

Calcium homeostasis: PTH (parathyroid, released by ↓ Ca²⁺): ↑ bone resorption (RANKL ↑), ↑ renal Ca²⁺ reabsorption (DCT, TRPV5), ↑ 1α-hydroxylase → ↑ calcitriol. Calcitriol (1,25-OH₂-D₃, renal activation): ↑ intestinal Ca²⁺ absorption (TRPV6/calbindin), ↑ bone resorption, ↑ renal Ca²⁺ retention. Calcitonin (thyroid C-cells, released by ↑ Ca²⁺): inhibits osteoclast ruffled border → ↓ resorption → ↓ Ca²⁺ (minor adult role).

Osteoporosis: T-score ≤ −2.5 (DEXA). Primary (postmenopausal type I: oestrogen withdrawal → ↑ RANKL → trabecular bone loss; senile type II: both cortical and trabecular). Secondary: glucocorticoids most common (suppress Wnt → ↓ osteoblast function; ↑ RANKL; ↓ intestinal Ca²⁺ → secondary hyperPTH → ↑ resorption). Treatment: bisphosphonates (alendronate — inhibit FPPS → osteoclast apoptosis, first-line), denosumab (anti-RANKL), teriparatide (PTH 1-34, intermittent → anabolic), romosozumab (anti-sclerostin, anabolic + anti-resorptive).

Joint Types and Synovial Fluid

Three structural joint types: fibrous (skull sutures — no movement); cartilaginous (synchondroses: hyaline cartilage, e.g., epiphyseal plates; symphyses: fibrocartilage, e.g., intervertebral discs, pubic symphysis — limited movement); synovial (diarthroses — major limb joints; freely movable).

Synovial joints: articular hyaline cartilage (type II collagen + aggrecan/PGs — 80% water, compressive viscoelasticity; no blood supply); synovial membrane (type A synoviocytes: phagocytic; type B: secrete hyaluronic acid + lubricin → fluid film and boundary lubrication); synovial fluid (ultrafiltrate + HA → lubricates + nourishes cartilage via diffusion pumping). Articular cartilage is avascular and aneural → limited repair capacity (no circulating MSC access; low chondrocyte cellularity and proliferative capacity; dense matrix barriers).