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Skeletal muscle is the largest organ system in mammalian organisms providing postural control and movement patterns of varying intensity. Through evolution, skeletal muscle fibers have evolved into three phenotype clusters defined as a motor unit which consists of all muscle fibers innervated by a single motoneuron linking varying numbers of fibers of similar phenotype. This fundamental organization of the motor unit reflects the fact that there is a remarkable interdependence of gene regulation between the motoneurons and the muscle mainly via activity-dependent mechanisms. These fiber types can be classified via the primary type of myosin heavy chain (MHC) gene expressed in the motor unit. Four MHC gene encoded proteins have been identified in striated muscle: slow type I MHC and three fast MHC types, IIa, IIx, and IIb. These MHCs dictate the intrinsic contraction speed of the myofiber with the type I generating the slowest and IIb the fastest contractile speed. Over the last ~35 years, a large body of knowledge suggests that altered loading state cause both fiber atrophy/wasting and a slow to fast shift in the contractile phenotype in the target muscle(s). Hence, this review will examine findings from three different animal models of unloading: (1) space flight (SF), i.e., microgravity; (2) hindlimb suspension (HS), a procedure that chronically eliminates weight bearing of the lower limbs; and (3) spinal cord isolation (SI), a surgical procedure that eliminates neural activation of the motoneurons and associated muscles while maintaining neurotrophic motoneuron-muscle connectivity. The collective findings demonstrate: (1) all three models show a similar pattern of fiber atrophy with differences mainly in the magnitude and kinetics of alteration; (2) transcriptional/pretranslational processes play a major role in both the atrophy process and phenotype shifts; and (3) signaling pathways impacting these alterations appear to be similar in each of the models investigated.

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The public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources gathering and maintaining the data needed, and completing and reviewing the collection of information. Send comments regarding this burden estimate or any other aspect to this collection of information, including suggestions for reducing the burden to, Department of Defense, Washington Headquarters Services, Directorate for Information 14. ABSTRACT Data from four studies of standard and prototype load-carriage equipment were analyzed to determine the effects of the weight borne by male and female load earners on time to traverse a 3.2-km course at maximal speed and on energy expenditure and kinetic and kinematic variables during externally paced walking at 4.8 km-hr " 1 . The equipment configurations included fighting, approach, and sustainment :oads, with masses varying from 12 kg to 50 kg. It was found that course completion times and energy expenditure were directly related to the weight earned. Kinetic variables, including ground and joint reaction forces, generally evidenced substantial linear relationships with :he weight earned. Increases in maximum ankle, knee and hip joint reaction forces approached 1 N for each 1 N increase in the weight. The effects of weight earned on the kinematic variables were more complex. They included evidence of adaptations in walking gait that are likely to aid the load earner in maintaining stability and in absorbing the increased forces associated with increased load on the body.

The evolutionarily conserved order of the skeletal muscle myosin heavy chain (MHC) genes and their close tandem proximity on the same chromosome are intriguing and may be important for their coordinated regulation. We investigated type II MHC gene regulation in slow-type muscle fibers undergoing a slow to fast MHC transformation in response to inactivity, 7 days after spinal cord isolation (SI) in rats. We examined the transcriptional products of both the sense and antisense strands across the IIa-IIx-IIb MHC gene locus. A strand-specific reverse transcription (RT)-PCR approach was utilized to study the expression of the mRNA, the primary transcript (pre-mRNA), the antisense RNA overlapping the MHC genes, and both the intergenic sense and antisense RNAs. Results showed that the mRNA and pre-mRNA of each MHC had a similar response to SI, suggesting regulation of these genes at the transcriptional level. In addition, we detected previously unknown antisense strand transcription that produced natural antisense transcripts (NATs). RT-PCR mapping of the RNA products revealed that the antisense activity resulted in the formation of three major products: aII, xII, and bII NATs (antisense products of the IIa, IIx, and IIb genes, respectively). The aII NAT begins in the IIa-IIx intergenic region in close proximity to the IIx promoter, extends across the 27-kb IIa MHC gene, and continues to the IIa MHC gene promoter. The expression of the aII NAT was significantly up-regulated in muscles after SI, was negatively correlated with IIa MHC gene expression, and was positively correlated with IIx MHC gene expression. The exact role of the aII NAT is not clear; however, it is consistent with the inhibition of IIa MHC gene transcription. In conclusion, NATs may mediate cross-talk between adjacent genes, which may be essential to the coordinated regulation of the skeletal muscle MHC genes during dynamic phenotype shifts.Skeletal muscle is highly adaptable when subjected to altered loading and hormone states. Its size, metabolic makeup, and contractile properties can all be altered to optimize function (1). Variability in contractile properties is achieved mainly by diversification in the motor protein myosin heavy chain (MHC), 2 where different isoforms are encoded by distinct genes (1, 2). Of this family of eight MHC genes, six are tandemly linked and span ϳ420 kb in the rat on chromosome 10, with embryonic MHC situated at the most 5Ј end, sequentially followed by IIa, IIx, IIb, neonatal, and extraocular MHC. ␤ (or type I) and ␣ MHCs are located tandemly on separate chromosomes (chromosome 14 in the rat); they span ϳ50 kb and are separated by 4.5 kb. Interestingly, the genomic order and orientation on the chromosomes of the MHC genes are conserved in all mammalian species, leading researchers to suspect that this organization might be an important feature in the strategy for the coordinated regulation of these genes (2-5).Types I, IIa, IIx, and IIb, in respective order of increasing ATPase activity, are the four predominately exp...