Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by selective loss of motor neurons and progressive muscle wasting. Growing evidence indicates that mitochondrial dysfunction, not only occurring in motor neurons but also in skeletal muscle, may play a crucial role in the pathogenesis. In this regard, the life expectancy of the ALS G93A mouse line is extended by creatine, an intracellular energy shuttle that ameliorates muscle function. Moreover, a population of patients with sporadic ALS exhibits a generalized hypermetabolic state of as yet unknown origin. Altogether, these findings led us to explore whether alterations in energy homeostasis may contribute to the disease process. Here, we show important variations in a number of metabolic indicators in transgenic ALS mice, which in all shows a metabolic deficit. These alterations were accompanied early in the asymptomatic phase of the disease by reduced adipose tissue accumulation, increased energy expenditure, and concomitant skeletal muscle hypermetabolism. Compensating this energetic imbalance with a highly energetic diet extended mean survival by 20%. In conclusion, we suggest that hypermetabolism, mainly of muscular origin, may represent by itself an additional driven force involved in increasing motor neuron vulnerability.

A general and efficient trnsfection proce- (12) was synthesized from L-ornithine through biscyanoethylation followed by reduction of the dinitrile; amino groups were protected as t-butoxycarbonyl (Boc) derivatives. In order for the lipid headgroup to be able to anchor itself in the minor groove of DNA, a spacer arm was required (11) between the hydrocarbon chains and the polyamine. Therefore, a glycine residue was linked to dioctadecylamine (benzyloxycarbonylglycyl-p-nitrophenol at 1 equiv plus triethylamine at 1.1 equiv in CH2Cl2 for 5 hr; H2, 10%o Pd/C in CH2Cl2/EtOH for 1 hr; 87% overall yield). See Fig. 1 for schematic

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