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Alzheimer's disease (AD) develops along a continuum that spans years prior to diagnosis. Decreased muscle function and mitochondrial respiration occur years earlier in those that develop AD; however, it is unknown what causes these peripheral phenotypes in a disease of the brain. Exercise promotes muscle, mitochondria, and cognitive health and is proposed to be a potential therapeutic for AD, but no study has investigated how skeletal muscle adapts to exercise training in an AD-like context. Utilizing 5xFAD mice, an AD model that develops ad-like pathology and cognitive impairments around 6 mo of age, we examined in vivo neuromuscular function and exercise adapations (mitochondrial respiration and RNA sequencing) before the manifestation of overt cognitive impairment. We found 5xFAD mice develop neuromuscular dysfunction beginning as early as 4 mo of age, characterized by impaired nerve-stimulated muscle torque production and compound nerve action potential of the sciatic nerve. Furthermore, skeletal muscle in 5xFAD mice had altered, sex-dependent, adaptive responses (mitochondrial respiration and gene expression) to exercise training in the absence of overt cognitive impairment. Changes in peripheral systems, specifically neural communication to skeletal muscle, may be harbingers for AD and have implications for lifestyle interventions, like exercise, in AD. Graphical Abstract Integrated model for the development of neuromuscular dysfunction in the AD-like pathology of 5xFAD mice. (A) At 3 mo of age, nerve-stimulated muscle function is normal across genotypes and sexes. (B) By as early as 4 mo of age, nerve-stimulated muscle function declines, and (C) corresponds to impaired sciatic nerve function in 5xFAD mice. Peripheral neuromuscular dysfunction (D) corresponds to an altered mitochondrial and transcriptional response of skeletal muscle to exercise training. (E) These peripheral phenotypes of the early AD-like pathology of 5xFAD mice were present in the absence of overt cognitive decline, particularly in male mice. Created in Biorender. [ABSTRACT FROM AUTHOR]

Nemaline myopathy (NM) is a congenital myopathy that can result in lethal muscle dysfunction and is thought to be a disease of the sarcomere thin filament. Recently, several proteins of unknown function have been implicated in NM, but the mechanistic basis of their contribution to disease remains unresolved. Here, we demonstrated that loss of a muscle-specific protein, kelch-like family member 40 (KLHL40), results in a nemaline-like myopathy in mice that closely phenocopies muscle abnormalities observed in KLHL40-deficient patients. We determined that KLHL40 localizes to the sarcomere I band and A band and binds to nebulin (NEB), a protein frequently implicated in NM, as well as a putative thin filament protein, leiomodin 3 (LMOD3). KLHL40 belongs to the BTB-BACK-kelch (BBK) family of proteins, some of which have been shown to promote degradation of their substrates. In contrast, we found that KLHL40 promotes stability of NEB and LMOD3 and blocks LMOD3 ubiquitination. Accordingly, NEB and LMOD3 were reduced in skeletal muscle of both Klh[l40.sup.-/-] mice and KLHL40-deficient patients. Loss of sarcomere thin filament proteins is a frequent cause of NM; therefore, our data that KLHL40 stabilizes NEB and LMOD3 provide a potential basis for the development of NM in KLHL40-deficient patients., Introduction Nemaline myopathies (NMs) encompass a set of genetically heterogeneous diseases that are defined pathologically by the presence of characteristic rod-like structures, called nemaline bodies, in myofibers (1). Clinically, presentation [...]

MicroRNAs modulate cellular phenotypes by inhibiting expression of mRNA targets. In this study, we have shown that the muscle-specific microRNAs miR-133a-1 and miR-133a-2 are essential for multiple facets of skeletal muscle function and homeostasis in mice. Mice with genetic deletions of miR-133a-1 and miR-133a-2 developed adult-onset centronuclear myopathy in type II (fast-twitch) myofibers, accompanied by impaired mitochondrial function, fast-to-slow myofiber conversion, and disarray of muscle triads (sites of excita-tion-contraction coupling). These abnormalities mimicked human centronuclear myopathies and could be ascribed, at least in part, to dysregulation of the miR-133a target mRNA that encodes dynamin 2, a GTPase implicated in human centronuclear myopathy. Our findings reveal an essential role for miR-133a in the main-tenance of adult skeletal muscle structure, function, bioenergetics, and myofiber identity; they also identify a potential modulator of centronuclear myopathies., Introduction Human centronuclear myopathies (CNMs) are a group of congenital myopathies characterized by muscle weakness and abnormal centralization of nuclei in muscle myofibers (1, 2). CNMs can be classified into [...]

Loss of the dystrophin-glycoprotein complex from muscle sarcolemma in Duchenne's muscular dystrophy (DMD) renders the membrane susceptible to mechanical injury, leaky to [Ca.sup.2+], and disrupts signaling, but the precise mechanism(s) leading to the onset of DMD remain unclear. To assess the role of mechanical injury in the onset of DMD, extensor digitorum longus (EDL) muscles from C57 (control), mdx, and mdxutrophin-deficient [mdx:utrn(-/-); dystrophic] pups aged 9-12 days were subjected to an acute stretch-injury or no-stretch protocol in vitro. Before the stretches, isometric stress was attenuated for mdx:utrn(-/-) compared with control muscles at all stimulation frequencies (P < 0.05). During the stretches, EDL muscles for each genotype demonstrated similar mean stiffness values. After the stretches, isometric stress during a tetanus was decreased significantly for both mdx and mdx:utrn(-/-) muscles compared with control muscles (P < 0.05). Membrane injury assessed by uptake of procion orange dye was greater for dystrophic compared with control EDL (P < 0.05), but, within each genotype, the percentage of total cells taking up dye was not different for the no-stretch vs. stretch condition. These data suggest that the sarcolemma of maturing dystrophic EDL muscles are resistant to acute mechanical injury. Duchenne's Muscular Dystrophy; mice; membrane damage