Biological sex determines skeletal muscle atrophy in response to cortical TDP-43 pathology

Background: Amyotrophic lateral sclerosis (ALS) is a fatal and incurable neurodegenerative condition. In ALS, wasting of skeletal muscle causes weakness, paralysis and ultimately, death due to respiratory failure. Diagnosis of ALS is a long process and delays in diagnosis are common, which impedes rapid provision of patient care and treatment. Additional tools or methodologies that improve early detection might help overcome the diagnostic delays and enhance survival and quality of life for people with ALS. In this study, we used a transgenic mouse model to create a detailed catalogue of skeletal muscle wasting with the goal of finding muscles that can be examined to enhance early diagnosis of ALS. Methods: Cortical pathology was induced by crossing CaMKIIa-tTA and tetO-hTDP-43ΔNLS transgenic mice (ΔNLS). Transgenic expression was induced at 30-days postnatal via removal of doxycycline diet. Mice were aged to 15-, 20-, 30- and 45-days post transgene induction. Microdissection was applied to isolate 22 individual hindlimb muscles for measurement of weight. Both males and females were used at all timepoints. Results: We found that male and female ΔNLS mice exhibited hindlimb skeletal muscle atrophy relative to controls. Multiply innervated muscles, also known as series-fibered muscles, were especially vulnerable to atrophy. The strongest predictor of the atrophic response across all hindlimb muscles was the extent to which any individual muscle was larger in males than females, known also as sexual dimorphism. In males, muscles that are usually larger in males compared to females experienced the most atrophy. Conversely, in females, muscles that are usually of similar size between males and females experienced the most atrophy. Segregating muscles based on whether they were more affected in males or females revealed that hip extensors, knee flexors, knee extensors, ankle dorsiflexors and ankle evertors were more affected in males. Hip adductors, hip rotators, hip flexors and ankle plantarflexors were more affected in females. Conclusions: Our results demonstrate that the difference in the size of skeletal muscles in males compared to females is the most powerful predictor of muscle atrophy in response to dying forward pathology. This indicates that sex is a strong determinant of skeletal muscle vulnerability in ALS. Our results provide new insights into determinants of skeletal muscle atrophy and may help inform selection of muscles for diagnostic testing of ALS patients.