Table 2.

Mouse models carrying ALS mutations specifically in the skeletal muscle.

Muscle-Specific ALS Mouse Models
Mouse Lines	Tissue Specificity	ALS–Gene Regulation	Phenotypic/ Disease Onset	Muscle Phenotype	Neurological Phenotype	References
Acta1CRE;Sod1flox/flox (mSod1KO)	skeletal muscle (actin -1)	mouse Sod1 deletion	- Onset: 6–8 months - Survival: >16–17 months	No muscle atrophy Increase weakness Increased regenerative muscle fibers	No NMJ degeneration Not increased ROS production Not decreased mitochondrial ATP production	[88]
SOD1G93A/mIgf-1 (muscle rescue)	SOD1G93A ubiquitous Igf-1 in muscle	human SOD1-G93A overexpression and mouse Igf-1 overexpression	- G93A:onset: 90 days survival: <145 days - G93A/mIgf-1: onset: 110 days survival: <175 days	Maintenance of muscle integrity	NMJs stabilization Reduced inflammation in the spinal cord Enhanced MN survival	[89]
MLC/SOD1G93A	skeletal muscle (specific regulatory elements from MLC)	human SOD1-G93A overexpression	- Muscle atrophy: 4 weeks - Functional Performance: 16 weeks - Survival: not indicated	Muscle atrophy Significant reduction in muscle strength Alterations in the contractile apparatus Mitochondrial dysfunction Alteration in fiber type composition and metabolism (fast-to-slow shift)	NMJ dismantlement Microgliosis Hypomyelination in the sciatic nerve No MN loss in ventral spinal cord	[17,90,91,92]
WT-hSOD1mus G93A-hSOD1mus G37R-hSOD1mus	skeletal muscle (chicken -actin)	human SOD1 overexpression	Similar phenotype in all cases - Onset: 8–10 months - Survival: shortened 10–16% (slow disease progression)	Muscle atrophy Limb weakness and paresis Motor deficits Lifespan shortening Adipose tissue waste	Causes fatal ALS-like syndrome: Severe loss of NMJ Decreased innervation Axonopathy Spinal cord atrophy Loss of MN	[18,87]
TDP-43 TG	skeletal muscle (creatine kinase 8)	human TDP-43 overexpression	- Onset: 36 weeks - Survival: >18 months	Increased serum levels of myogenic enzymes Degenerative myofibers via ER stress Myotoxicity featuring tubular aggregates and TDP-43-positive inclusions	Not described	[93]
Pax7IREScreTardbpflox/WT	Pax7 lineage	1 copy of mouse Tdp-43 deletion in MPCs and progeny	No phenotype in the adult but smaller myofibers after muscle damage-induced regeneration	TDP-43 is essential for skeletal-muscle-cell differentiation in culture and required for skeletal-muscle regeneration	Not described	[94]
MRL/MpJ	“super-healing” mouse model with siRNA	mouse Sod1 or Cat depletion (in vitro silencing of MPCs)	Great regenerative capacity for repair of many tissues	Impaired myogenic potential of MPCs A role for antioxidants in muscle repair	Not described	[80]

Abbreviations: SOD1: superoxide dismutase 1; G93A: SOD1 Gly⁹³ → Ala described mutation; G37R: SOD1 Gly³⁷ → Arg described mutation; Acta1: actin α 1 gene; Igf-1: insulin-like growth factor isoform 1 gene; MLC: skeletal muscle-specific regulatory elements from rat myosin light chain (MLC)-1/3 locus; Tardbp: TAR DNA binding protein gene (TDP-43); Cat: catalase gene; MRL/MpJ: Murphy Roths Large mouse line; NMJ: neuromuscular junction; MN: motor neuron; MPC: muscle progenitor cells; WT: wild-type; KO: knock-out; h: human; mus: mouse; m: muscle.