6.7 Muscular Contraction & Carbohydrate/Protein/Lipid Metabolism

Sliding Filament Theory

Muscle contraction is explained by the sliding filament theory: thick myosin filaments and thin actin filaments slide past each other, shortening the sarcomere without the filaments themselves changing length. The sarcomere is the functional unit of striated muscle, bounded by Z lines; the structural landmarks include the A band (length of the thick filament, constant during contraction), I band (thin filaments only, shortens), and H zone (thick filaments only, shortens).

Cross-Bridge Cycle

Each myosin head forms a cross-bridge with actin and goes through the following cycle, requiring ATP:

1. ATP binds myosin head → release of actin (cross-bridge detachment).
2. ATP hydrolysis → myosin head cocks into high-energy 'armed' position (ADP + Pi remain bound).
3. Cross-bridge formation — myosin head binds a new actin monomer (if Ca2+ is present and tropomyosin shifted).
4. Power stroke — Pi release triggers conformational change, pulling actin toward the M line.
5. ADP release completes the cycle.

The cycle continues as long as Ca2+ and ATP are available. Rigor mortis occurs after death when ATP is exhausted and myosin heads remain attached to actin.

Regulation by Ca2+ and Troponin/Tropomyosin

In relaxed skeletal muscle, tropomyosin blocks the myosin-binding sites on actin. On excitation, Ca2+ binds troponin C, causing a conformational shift that moves tropomyosin away from the binding sites, allowing cross-bridge cycling. When Ca2+ is pumped back into the SR by SERCA, troponin C releases Ca2+ and tropomyosin returns to its blocking position.

Excitation-Contraction Coupling

Excitation-contraction (E-C) coupling links membrane depolarization to cross-bridge cycling:

1. AP propagation along the sarcolemma and into T-tubules (transverse tubules).
2. Dihydropyridine receptor (DHPR), an L-type voltage-gated Ca2+ channel in the T-tubule, senses depolarization. In skeletal muscle, DHPR mechanically interacts with the ryanodine receptor (RyR1) on the SR terminal cisternae, opening it and releasing Ca2+ into the cytosol (mechanical coupling, no Ca2+ influx required).
3. In cardiac muscle, DHPR (L-type) allows a small Ca2+ influx (Ca2+-induced Ca2+ release, CICR) that triggers RyR2 to release a much larger Ca2+ pool from the SR.
4. Ca2+ binds troponin C → cross-bridge cycling → contraction.
5. Relaxation: SERCA pumps Ca2+ back into the SR (ATP-dependent); in cardiac muscle, the Na+/Ca2+ exchanger (NCX) also extrudes Ca2+.

Sources of ATP for Muscle

Muscle uses ATP in four ways during activity:

1. Stored ATP — very brief (seconds).
2. Creatine phosphate — phosphorylates ADP to ATP via creatine kinase; supports ~10 seconds of maximal effort.
3. Glycolysis — anaerobic, fast, produces lactate; supports ~1–2 minutes of intense activity.
4. Oxidative phosphorylation — aerobic, slow, sustainable for hours; dominant in endurance activity.

Neuromuscular Junction (NMJ)

The NMJ is the synapse between a motor neuron and a skeletal muscle fiber:

1. AP reaches the presynaptic terminal, opens voltage-gated Ca2+ channels, and triggers acetylcholine (ACh) release into the synaptic cleft.
2. ACh binds nicotinic (N2) receptors (ligand-gated Na+ channels) on the motor end plate, producing an end-plate potential (EPP) that summates to threshold and fires a muscle AP.
3. Acetylcholinesterase (AChE) in the synaptic cleft hydrolyzes ACh, terminating the signal.

Drugs/toxins:

• Curare (d-tubocurarine) — competitive N2 antagonist → flaccid paralysis.
• Succinylcholine — N2 agonist that does not dissociate → sustained depolarization (phase I block) → flaccid paralysis.
• Botulinum toxin — prevents ACh release (cleaves SNARE proteins) → flaccid paralysis.
• Organophosphates — inhibit AChE → ACh accumulation → initial fasciculations then depolarizing block.
• Myasthenia gravis — autoimmune antibodies against N2 receptors → fatigable weakness; improved by AChE inhibitors (pyridostigmine).
• Lambert-Eaton syndrome — antibodies against presynaptic P/Q-type Ca2+ channels → improved with repeated contraction (warm-up).

Skeletal vs Cardiac vs Smooth Muscle

Smooth Muscle Specialization

Smooth muscle lacks troponin. Ca2+ binds calmodulin; the Ca2+-calmodulin complex activates myosin light-chain kinase (MLCK), which phosphorylates myosin regulatory light chain, enabling cross-bridge cycling. Myosin light-chain phosphatase (MLCP) dephosphorylates myosin, producing relaxation. In latch state, myosin remains attached without cycling, sustaining tone with minimal ATP use — important in vascular smooth muscle.

Carbohydrate Metabolism

Glycolysis (Cytoplasm)

Glycolysis converts glucose (6C) to two pyruvate (3C) molecules, producing a net 2 ATP (substrate-level phosphorylation) and 2 NADH. Key regulatory enzymes: hexokinase/glucokinase, phosphofructokinase-1 (PFK-1, rate-limiting), pyruvate kinase. PFK-1 is stimulated by AMP and fructose-2,6-bisphosphate; inhibited by ATP and citrate.

In anaerobic conditions, pyruvate is reduced to lactate (regenerating NAD+). In aerobic conditions, pyruvate enters mitochondria, is converted to acetyl-CoA by pyruvate dehydrogenase (PDH), and enters the Krebs cycle.

Krebs Cycle (Mitochondrial Matrix)

Acetyl-CoA (2C) combines with oxaloacetate (4C) to form citrate (6C). Two decarboxylations and four oxidations yield 2 CO2, 3 NADH, 1 FADH2, 1 GTP per acetyl-CoA. The cycle is fueled by carbohydrates, fats (via beta-oxidation), and proteins (via acetyl-CoA or intermediates).

Oxidative Phosphorylation (Inner Mitochondrial Membrane)

NADH and FADH2 donate electrons to the electron transport chain (Complexes I–IV). Electrons flow to O2 (reduced to H2O). Protons are pumped into the intermembrane space, generating an electrochemical gradient. ATP synthase (Complex V) uses proton flow back into the matrix to phosphorylate ADP — chemiosmotic coupling. Yield: ~2.5 ATP per NADH, ~1.5 ATP per FADH2; total ~30–32 ATP per glucose.

Gluconeogenesis, Glycogen, Hormonal Control

• Gluconeogenesis — liver and kidney synthesize glucose from lactate, glycerol, alanine, and other amino acids via pyruvate carboxylase (mitochondrial, requires biotin), PEPCK, fructose-1,6-bisphosphatase, and glucose-6-phosphatase. Stimulated by glucagon, cortisol; inhibited by insulin.
• Glycogenesis/glycogenolysis — glycogen synthase (insulin-stimulated) vs. glycogen phosphorylase (glucagon/epinephrine-stimulated via cAMP/PKA). Liver glycogen maintains blood glucose; muscle glycogen fuels local contraction.

Protein Metabolism

Amino acids undergo transamination (catalyzed by aminotransferases like ALT and AST, requiring pyridoxal phosphate/vitamin B6) to transfer amino groups to alpha-ketoglutarate, forming glutamate. Glutamate is oxidatively deaminated by glutamate dehydrogenase to release NH4+. Ammonia is converted to urea in the urea cycle (liver mitochondria and cytosol), exported to kidney for excretion. Rate-limiting enzyme: carbamoyl phosphate synthetase I (requires N-acetylglutamate). Urea cycle disorders cause hyperammonemia.

Essential amino acids (9 in adults: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine) cannot be synthesized and must come from diet.

Lipid Metabolism

• Beta-oxidation — mitochondrial oxidation of fatty acyl-CoA to acetyl-CoA (each cycle removes 2 carbons, yields 1 FADH2, 1 NADH). Carnitine shuttle (CPT-I, CPT-II) transports long-chain fatty acids into mitochondria; malonyl-CoA (from fatty acid synthesis) inhibits CPT-I.
• Ketogenesis — in hepatic mitochondria during fasting, acetyl-CoA from beta-oxidation forms acetoacetate and beta-hydroxybutyrate ('ketone bodies'), exported to brain, heart, muscle. Crucial during prolonged fasting; overproduction in uncontrolled diabetes causes ketoacidosis.
• Lipogenesis — insulin stimulates fatty acid synthesis from acetyl-CoA (citrate shuttle, acetyl-CoA carboxylase rate-limiting, producing palmitate) and triglyceride storage in adipose.
• Lipolysis — glucagon/epinephrine activate hormone-sensitive lipase via cAMP/PKA, releasing free fatty acids and glycerol.

Integration: The Liver as Metabolic Hub

The liver is the central integrator:

• Fed state — stores glycogen, synthesizes triglycerides, processes dietary amino acids.
• Fasting — glycogenolysis, then gluconeogenesis; beta-oxidation; ketogenesis.
• Prolonged fasting/starvation — increased ketogenesis to fuel brain, breakdown of muscle protein to provide gluconeogenic amino acids.
• Hormonal orchestration — insulin promotes storage and anabolism; glucagon, cortisol, epinephrine, and GH promote mobilization and catabolism.

Metabolic Disorder Highlights

• Pyruvate dehydrogenase deficiency — lactic acidosis, neurologic defects.
• McArdle disease — muscle glycogen phosphorylase deficiency → exercise intolerance, cramps, myoglobinuria.
• Pompe disease — lysosomal acid alpha-glucosidase deficiency → lysosomal glycogen accumulation.
• Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency — impaired fasting beta-oxidation → hypoketotic hypoglycemia.
• Phenylketonuria (PKU) — phenylalanine hydroxylase deficiency → elevated phenylalanine; managed with low-Phe diet.
• Type 1 diabetes — absolute insulin deficiency → hyperglycemia, ketoacidosis, lipolysis, proteolysis.

The integration of muscle contraction and metabolism is critical for the PA-CAT Physiology content: contraction requires ATP supplied by glycolysis, oxidative phosphorylation, and creatine phosphate; chronic metabolic imbalance (e.g., diabetes) impairs muscle function and shifts substrate utilization.